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Pathogenic effect of interleukin-17A in induction of Sjögren’s syndrome-like disease using adenovirus-mediated gene transfer

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Title:
Pathogenic effect of interleukin-17A in induction of Sjögren’s syndrome-like disease using adenovirus-mediated gene transfer
Creator:
Nguyen, Cuong Q.
Yin, Hongen
Lee, Byung Ha
Carcamo, Wendy C.
Chiorini, John A.
Peck, Ammon B.
Publisher:
BioMed Central Ltd
Publication Date:
Language:
English

Notes

Abstract:
Introduction: Sjögren’s syndrome (SS) involves a chronic, progressive inflammation primarily of the salivary and lacrimal glands leading to decreased levels of saliva and tears resulting in dry mouth and dry eye diseases. Seminal findings regarding TH17 cell populations that secrete predominantly interleukin (IL)-17A have been shown to play an important role in an increasing number of autoimmune diseases, including SS. In the present study, we investigated the function of IL-17A on the development and onset of SS, Methods: Adenovirus serotype 5 (Ad5) vectors expressing either IL-17A or LacZ were infused via retrograde cannulation into the salivary glands of C57BL/6J mice between 6-8 weeks of age or between 15-17 weeks of age. The mice were characterized for SS phenotypes. Results: Disease profiling indicated that SS-non-susceptible C57BL/6J mice whose salivary glands received the Ad5-IL17A vector developed a SS-like disease profile, including appearance of lymphocytic foci, increased cytokine levels, changes in antinuclear antibody profiles, and temporal loss of saliva flow. Conclusions: Induction of SS pathology by IL-17A in SS-non-susceptible mice strongly suggests that IL-17A is an important inflammatory cytokine in salivary gland dysfunction. Thus, localized anti-IL17 therapy may be effective in preventing glandular dysfunction.
Funding:
Publication of this article was funded in part by the University of Florida Open-Access publishing Fund.

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Pathogenic effect of interleukin-17A in induction of Sjogren's syndrome-like disease
using adenovirus-mediated gene transfer

Cuong Q. Nguyen ^^^'', Hongen Yin ^, Byung Ha Lee ^, Wendy C. Carcamo ^, John A. Chiorini ^
& Ammon B. Peck ^''^

^ Eli and Edythe L. Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA
^Department of Chemical Engineering, Massachusetts Institute of Technology, 77
Massachusetts Ave, E25-545, Cambridge MA 02139, USA
^ Department of Oral Biology, University of Florida College of Dentistry, 1600 SW Archer Rd,
Gainesville, Florida 32610, USA
''Center for Orphan Autoimmune Disorders, University of Florida College of Dentistry, 1600 SW
Archer Rd, Gainesville, Florida 32610, USA
^National Institute of Dental and Craniofacial Research, NIH, 10 Center Drive MSC 1190,
Bethesda, Maryland 20892, USA
^Department of Pathology, Immunology & Laboratory Medicine, University of Florida
College of Medicine, 1600 SW Archer Rd, Gainesville, Florida 32610, USA

Running title: The role of IL-17A in Sjogren's Syndrome

Address correspondence:
Cuong Q. Nguyen, PhD
Department of Oral Biology
PO Box 100424, College of Dentistry
University of Florida, Gainesville, Florida 32610 USA
Telephone: 352-273-8865 FAX: 352-273-8829
E-mail: Nguyen@pathology.ufl.edu
1


ABSTRACT:
Introduction: Sjogren's syndrome (SS) involves a chronic, progressive inflammation primarily



of the salivary and lacrimal glands leading to decreased levels of saliva and tears resulting in



dry mouth and dry eye diseases. Seminal findings regarding Th17 cell populations that secrete



predominantly interleukin (IL)-17A have been shown to play an important role in an increasing



number of autoimmune diseases, including SS. In the present study, we investigated the



function of IL-17A on the development and onset of SS,



Methods: Adenovirus serotype 5 (Ad5) vectors expressing either IL-17A or LacZ were infused



via retrograde cannulation into the salivary glands of C57BL/6J mice between 6-8 weeks of age



or between 15-17 weeks of age. The mice were characterized forSS phenotypes.



Results: Disease profiling indicated that SS-non-susceptible C57BL/6J mice whose salivary



glands received the Ad5-IL17A vector developed a SS-like disease profile, including



appearance of lymphocytic foci, increased cytokine levels, changes in antinuclear antibody



profiles, and temporal loss of saliva flow.



Conclusions: Induction of SS pathology by IL-17A in SS-non-susceptible mice strongly



suggests that IL-17A is an important inflammatory cytokine in salivary gland dysfunction. Thus,



localized anti-IL17 therapy may be effective in preventing glandular dysfunction.
2


INTRODUCTION




Sjogren's syndrome (SS) is a chronic, systemic autoimmune disease characterized most




notably by development of dry eyes and dry mouth manifestations, indicative of secretory




dysfunction of the lacrimal and salivary glands [1-3]. Although the etiology of SS remains




unknown, intensive studies of an ever expanding number of animal models is beginning to




unravel the genetic, molecular and immunological basis for this disease[1]. Previous studies




have implicated critical roles for both interferon-y (IFN-y) and interleukin (IL)-4 in development




and onset of SS-like disease in NOD/LtJ and C57BL/6.NOD-/Aecf/Aec2 mice [4, 5], strongly




suggesting involvement of ThI and Th2 cell populations, respectively. While IFN-y regulates




cell-mediated immunity through activation of macrophages, NK cells and CD8'^ T cells, this




cytokine appears to predispose these SS-susceptible mice by retarding salivary gland




organogenesis, especially proliferation of acinar tissue [5]. This delay in acinar cell maturation




has been postulated to prevent expression of cellular antigens at the critical time of self-




tolerance, resulting in inefficient clonal deletion of acinar tissue-reactive T cells. In contrast to




the role of IFN-y both prior to and during development of SS, IL-4 appears to be essential during




development of adaptive immunity and subsequent onset of glandular dysfunction. Specifically,




IL-4 was shown to be necessary for proper isotypic switching, regulating B lymphocyte




synthesis of pathogenic IgGI anti-muscarinic acetylcholine type III receptor (M3R)




autoantibodies [6, 7].




Although these earlier studies have implicated both ThI and Th2 cell-associated




functions in the development and onset of clinical SS, recent identification of the CD4'^ ThI 7




memory cells within the lymphocytic focus (LF) of lacrimal and salivary glands of SS^




C57BL/6.NOD-/Aec'//Aec2 mice, as well as minor salivary glands of human SS patients, greatly




expands the potential complexity in deciphering the autoimmune response underlying SS [8, 9].




The ThI7 cell population, while clearly a subset of CD4'^ memory effector T cells, appears to be






3


distinct from, and unrelated to, either the ThI orTH2 cell lineages [10-14]. ThI 7 effector cells



secrete at least one of the six cytokines belonging to the IL-17 family, i.e., IL-17A, IL-17B, IL-



17C, IL-17D, IL-25 and/or IL-17F; however, IL-17A, the signature cytokine, has received the



greatest attention in studies of autoimmune diseases [15]. The I LI 7 cytokines are potent pro-



inflammatory molecules, actively involved in tissue inflammation via induction of pro-



inflammatory cytokine and chemokine expressions [16]. In addition, IL-17 is involved in the



mobilization, maturation and migration of neutrophils via the release of IL-8 at the site of injury



[17]. Interestingly, IL-17A is known to regulate Foxp3+ TReg cells and vice versa [18].



While ThI7 cells have been implicated in several autoimmune diseases (e.g., Crohn's



disease [19, 20], experimental autoimmune encephalomyelitis (EAE) [21], collagen-induced



arthritis CIA) [21], SS [8] and others [2, 3]), this characteristic may require signaling from ThI



cells already present in the lesion [3]. In any event, recent observational studies in SS patients



and animal models of primary SS have identified the presence of IL-17A and its activating



cytokine IL-23 in the lymphocytic infiltrates of the exocrine glands, as well as higher levels of



circulating IL-17A in both sera and saliva [8], raising the question of the importance of IL-17 in



SS. Thus, the goals of the present study were to determine whether IL-17A can directly



influence the pathology leading to the onset of SS-like disease by administrating exogenous IL-



17A to the salivary glands at specific time points.
4


MATERIALS AND METHODS




Animals




SS non-susceptible C57BL/6J mice were bred and maintained under specific pathogen-free




conditions. The animals were maintained on a 12 hr light-dark schedule and provided food and




acidified water ad libitum. At times indicated in the text, mice were euthanized by cervical




dislocation following deep anesthetization with isoflurane, after which organs were freshly




explanted for analyses. Both the breeding and use of these animals for the present studies




were approved by the University of Florida's lACUC and IBC. Salivary glands of mice were




cannulated with mouse IL-17A-expressing Ad5-IL17A vector using retrograde injections at either




7 weeks (wks) of age (n=11) or 16 wks of age (n=8). In addition, mice at 6 wks (n=4) and 15




wks (n=4) were randomly selected and used as pre-treated or baseline analysis. Age- and sex-




matched control C57BL/6J mice (n=10 per age group) received the Ad5-LacZ control vector




using the same protocols.




Production of Ad5-LacZ and Ad5-IL17A vectors




The recombinant adenovirus vectors used in this study were generously provided by Dr. Jay K.




Kolls (Children's Hospital of Pittsburgh, Pittsburgh, PA). These vectors are based on the first




generation adenovirus serotype 5 (Ad5) and shown to produce their appropriate and functional




mouse IL- 17A and LacZ products [22-24]. To obtain sufficient viral vectors for the present




studies, each recombinant vector was amplified in HEK293 cells, purified by two rounds of CsCI




gradient centrifugation, then dialyzed against 100 mM Tris-HCI (pH 7.4), 10 mM MgCb and 10%




(v/v) glycerol, as described elsewhere [25].




Retrograde salivary gland cannulation of Ad5-LacZ or Ad5-IL17A vectors




Previous studies have demonstrated that retrograde salivary gland cannulation is an effective




method to direct local gene expression in the salivary glands [26-28]. In brief, prior to




cannulation, each mouse was anesthetized with a ketamine:xylazine mixture (100 mg/mL, 1






5


mL/kg body weight; Fort Dodge Animal Health, Fort Dodge, lA) and xylazine (20 mg/mL, 0.7




mL/kg body weight; Phoenix Scientific, St. Joseph, MO)) via intramuscularly. Stretched PE-10




polyethylene tubes were inserted into each of the two openings of the salivary ducts. After




securing the cannulas, the mouse received an intramuscular injection of atropine (1 mg/kg),




followed 10 minutes later by a slow, steady injection of viral vector. Each salivary gland




received 50 |jl of vector solution containing 10'^ viral particles). The cannulas were removed 5




minutes later to ensure successful cannulation.




Measurement of saliva flow




To measure stimulated saliva flow, individual non-anesthetized mice were weighed and given an




i.p. injection of 100 |jl of PBS containing isoproterenol (0.02 mg/ml) and pilocarpine (0.05




mg/ml). Saliva was collected for 10 min from the oral cavity of individual mice using a




micropipette starting 1 min after injection of the secretagogue. The volume of each saliva sample




was measured. Prior to vector cannulation and again at each time-point designated in the text,




saliva and sera were collected from each mouse. Samples were stored at -80C until analyzed.




Determination of cytokines levels:




Measurements of IL-6 and IL-17A cytokine levels in sera samples were performed by an




independent contractor (Millipore, Billerica, MA) using Luminex platform.




Intracellular cytokine staining and flow cytometric analysis




Spleens were freshly explanted, gently minced through stainless steel sieves, suspended in




phosphate buffered saline (PBS) and centrifuged (1200rpm for 5 minutes). Erythrocytes were




lysed by 7 minute incubation in 0.84% NH4CI. The resulting leukocyte suspensions were




washed two times in PBS, counted and resuspended inculture media (RPMI 1640 medium, 10%




FBS, 2 mM L-glutamine, 0.05 mM |3-mercaptoethanol) at a density of 2 x 10^ cells/ml. One




million cells were pipetted to individual wells of a 24-well microtiter plate pre-coated with anti-




CD3 (10 |jg/ml) and anti-CD28 antibodies (2 |jg/ml) forT cell activation. Cells were incubated for




5 hrs with Leukocyte Activation Cocktail containing GolgiPlug (2 |jl/ml). Collected cells were




6


fixed and permeabilized using Cytofix/CytopermFixation/Permeabilization. Flow cytometric




acquisition for intracellular staining was performed following staining with PE-Cy5-conjugated




anti-mouse CD4, FITC-conjugated anti-IFN-y and PE-conjugated anti-IL-17AA. The cells were




counted on a FACSCalibur (BD, Franklin Lakes, NJ) and analyzed by FCS Express (De Novo




Software, Los Angeles, CA).




Histology




Following euthanasia, whole salivary glands containing submandibular, sublingual, and parotid




glands were surgically removed from each mouse and placed in 10% phosphate-buffered




formalin for 24 hrs. Fixed tissues were embedded in paraffin and sectioned at 5 |jm thickness.




Paraffin-embedded sections were de-paraffinized by immersing in xylene, followed by




dehydrating in ethanol. The tissue sections were prepared and stained with hematoxylin and




eosin (H&E) dye. Stained sections were observed under a microscope for glandular structure




and leukocyte infiltration determination. A double-blinded procedure was used to enumerate




leukocytic infiltrations (lymphocytic foci) in the histological sections of salivary glands.




Lymphocytic foci (LF) were defined as aggregates of >50 leukocytes quantified per each




histological section. Calculations were based on one histological section per mouse.




Immunofluorescent staining for CD3+T cells and B220+B cells




Histological sections of salivary glands were incubated with rat anti-mouse B220 (BD




Pharmingen, San Jose, CA) and goat anti-mouse CD3 (Santa Cruz Biotechnology, Santa Cruz,




CA), followed by incubation with Texas Red-conjugated rabbit anti-rat IgG (Biomeda, Foster




City, CA) and FITC-conjugated rabbit anti-goat IgG (Sigma-Aldrich, St. Louis, MO). The slides




were mounted with DAPI-mounting medium (Vector Laboratories, Burlingame, CA). Sections




were observed at 200X magnification using a Zeiss Axiovert 200M microscope.and images




were obtained with AxioVs40 software (Ver. 4.7.1.0, Zeiss) (Carl Zeiss, Thornwood,.




Enumeration of B, T cells and total number of nuclei in the LF were performed using Mayachitra




imago software (Mayachitra, Inc, Santa Barbara, CA)




7


Immunohistochemical staining for IL17A in salivary glands




Immunohistochemical staining for IL17A were carried out as previously described [8]. In brief,




paraffin-embedded salivary glands were deparaffinized by immersion in xylene, followed by




antigen retrieval with 10 mM citrate buffer, pH 6.0. Tissue sections were incubated overnight at




4C with anti-IL-17A antibody (Santa Cruz Biotechnology Santa Cruz, CA). Isotype controls




were done with rabbit IgG. The slides were incubated with biotinylated goat anti-rabbit IgG




followed by horseradish peroxidase-conjugated strepavidin incubation using the Vectastain




ABC kit. The staining was developed by using diaminobenzidine substrate (Vector Laboratories,




Burlingame, CA), and counterstaining was performed with hematoxylin. Sections were




observed at 200X magnification using a Zeiss Axiovert 200M microscope. And images were




obtained with AxioVs40 software (Ver. 4.7.1.0, Zeiss) (Carl Zeiss, Thornwood). Enumeration of




IL17A-positive cells was performed on the entire histological sections of the whole salivary




glands using Mayachitra imago software (Mayachitra, Inc, Santa Barbara, CA), although




lymphocytic infiltrations are normally seen only in the submandibular glands.













Detection of antinuclear antibodies (ANA) in the sera




ANA in the sera of mice were detected using HEp-2 ANA kit (INOVA Diagnostics, Inc, San




Diego, CA). All procedures were performed per manufacturer's instructions. In brief, HEp-2




fixed substrate slides were overlaid with appropriate mouse sera diluted 1:40, 1:80 and 1:160.




Slides were incubated for 1 hr at room temperature in a humidified chamber. After three




washes for five minutes with PBS, the substrate slides were covered with Alexa 488-conjugated




goat anti-mouse IgG (H/L) (Invitrogen Inc, Carlsbad, CA) diluted 1:100 for 45 min at room




temperature. After three washes, fluorescence was detected by fluorescence microscopy at




200X magnification using a Zeiss Axiovert 200M microscope and all images were obtained with




AxioVs40 software with constant exposure of 0.3 seconds (Carl Zeiss, Thornwood, NY).




8


Negative controls are secondary antibody only and positive controls are standard serum with



nuclear speckled pattern provided with the kits. Data presented in the results are from slides



using 1:40 dilutions of sera from each experimental group.








Statistical analyses



Statistical evaluations were determined by using Mann-Whitney U test generated by the



GraphPad InStat software (GraphPad Software, La Jolla, CA). The two-tailed p value <0.05 was



considered significant.
9


RESULTS
Induction of IL-17 A and IL-6 cytokine levels in sera following transduction with Ad5-




IL17A vector




Adenoviral vectors have been reported to show peak gene expressions around day 5




post-infusion which then persist for approximately 2 wks [29]. In the current study,




immunohistochemical staining for the presence of LacZ protein in the infused salivary glands




demonstrated that optimal transduction efficiency was approximately 26 5% at 2 wks post-




infusion which decreased to 15 3% by 9 wks post-infusion. The cells within the salivary




glands positive for LacZ expression were predominantly ductal cells, as expected, and acinar




cells (data not shown), indicating the virus was capable of passing through the ducts.




To determine if transduction of salivary glands with IL-17A alters the serum cytokine




profiles, serum preparations were assessed for temporal changes in pro-inflammatory cytokine




levels. Sera of treated mice were collected at days 5 and 12 post-treatment to determine the




efficacy of the IL-17A expressing viral vectors to affect cytokine secretions. As shown in Figure




1, C57BL/6J mice treated with the Ad5-IL17A vector at 10'^ viral particles per salivary gland




exhibited a marked increase in the levels of serum IL-17A compared to baseline levels or with




C57BL/6J mice receiving the control Ad5-LacZ vector at 10'^ viral particles per salivary gland,




demonstrating the efficacy of this viral vector to produce IL-17A. In addition, Ad5-IL17A-treated




C57BL/6J mice also secreted elevated amounts of the IL-17A-related cytokine IL-6 following




cannulation. Thus, the vectors gain access into the glands and apparently secrete IL-17A in




quantities that elevate systemic levels.








Increased numbers of IL-17A-producing CD4+ T cells in the spleens of Ad5-1L17A




transduced mice
10


As mentioned previously, salivary glands were cannulated with Ad5-IL17A vector at



either 7 wks or 16 wks of age. The time points chosen are based on extensive studies of the



development and onset of disease in our C57BL/6.NOD-/Aec'//Aec2 mouse model of SS [1-3, 30,



31]. The two time points selected represent the innate and adaptive immune response phases,



respectively, in the disease model, thus they were chosen to mimic these changes in the



parental C57BL/6 mouse. Microarray analyses examined the temporal differential gene



expression of salivary and lacrimal glands of C57BL/6 mice revealed gradual change in



pathophysiological related genes from 16-20 wks of age, concomitantly, leukocyte infiltration in



the exocrine glands is often observed at these ages [32, 33]. Thus, it is important to examine



the role of IL17A in the development of SS at prior and post to any pathophysiological changes.



Mice treated with Ad5-IL17A or Ad5-LacZ at either 7 wks or 16 wks of age were



euthanized at 26 and 27 wks of age, i.e. 19 wks and 11 wks post-treatment, respectively.



Splenocytes were isolated from individual mice and examined for the number of IFN-y and IL-



17A secreting CD4+T cells. Representative data, presented in Figures 2B &C, revealed that



the number of IL-17A secreting CD4+T cells in the spleens of mice receiving the Ad5-IL17A



vector at 7 wks of age was approximately 2-fold higher than mice receiving the control Ad5-



LacZ vector, while the number of IFN-y secreting CD4+T cells was approximately half at time of



analysis. Similarly, the number of IL-17A secreting CD4+T cells in the spleens of mice receiving



the Ad5-IL17A vector at 16 wks of age was approximately 7-fold higher than mice receiving the



control Ad5-LacZ vector, while the number of IFN-y secreting CD4+T cells was less than 50% at



time of analysis (Figure 2E & F). Results of a similar analysis with untreated mice performed



one wk prior to vector cannulations are presented in Figures 2A & D. These data suggest that



even though the Ad5 vector is considered locally restricted, the effect in C57BL/6 J mice



appeared systematic. More importantly, the systemic effects of IL17A in Ad5 appears to be



correlate with the duration of gene expression after vector cannulation as evidenced by the 2-



fold increase in the levels of IL-17A secreting cells at 19 wks post-treatment in younger mice but



11


a 7-fold increase at 11 wks post-treatment in the older group. However, one cannot rule out the




possibility that different efficacies are achieved based on the status of disease development in




different ages of mice.








Induction of SS immune-pathology in C57BL/6 mice following treatment with Ad5-IL17A




vector




Lymphocyte infiltration of the salivary and/or lacrimal glands is a critical criterion for identification




of the autoimmune phase of SS in both human and animal models. Although the number of LF




present in the salivary and lacrimal glands does not often correlate directly with disease or its




severity, SS patients and NOD-derived mouse strains exhibiting SS-like disease typically have




lymphocytic infiltrates in theirsalivary glands. IL-17A appears to play a critical role in the




development of LF and has recently been found to be present within LF in both SS patients and




animal models [8]. Salivary glands of C57BL/6J mice following cannulation with Ad5-IL17A




vector were examined for the presence of infiltrating leukocytes. Salivary glands retrieved from




C57BL/6J mice treated with Ad5-LacZ vector at either 7 or 16 wks of age revealed that 10% (1




of 10) in each group had evidence of glandular infiltrations (Figure 3A, B, G, H, Table 1). This




observation is consistent with the number of healthy, untreated C57BL/6J mice expected to




have infiltration of the salivary glands [8]. In contrast, salivary glands from C57BL/6J mice




treated with Ad5-IL17A vector at 7 wks of age showed infiltrations in 91% (10 of 11) with the




mean LF per histological section numbering 4 + 1.32, while salivary glands from C57BL/6J mice




treated with Ad5-IL17A vector at 16 wks of age revealed infiltrations in 75% (6 of 8) with a mean




LF number per histological section of 2 + 0.83 (Table 1).




Besides the number of LF detected in the salivary glands of the experimental animals,




immunofluorescent staining to detect B and T cells revealed further differences in the cellular




composition of the infiltrations between mice administered Ad5-IL17A at an early or late stage.




At time of euthanasia, C57BL/6J mice treated with Ad5-IL17A vector at 7 wks of age generally




12


exhibited smaller foci containing fewer IL-17 positive cells compared to mice receiving the




vector at 16 wks of age (Figure 3 C-F & l-L). Consistent with previous observation, the smaller




foci in mice treated at 7 wks of age may have resulted from the longer duration of time after




cannulation (19 wks) reflecting the decreases in IL-17A serum levels and IL-17A- positive cell




numbers. Detailed examination of IL-17A-positive cells revealed that a majority of IL-17A cells




are present in the LF and ductal cells with smaller percentage of positive cells found in the




epithelium and acinar cells. Nevertheless, these data support the concept that formation and




maintenance of LF are due, in part, to the expression levels of IL17A in the salivary glands.








Changes in ANA profiles following instillation of the Ad5-IL-17A vector




With the appearance of B and T lymphocytes within the salivary glands of Ad5-IL17A treated




C57BL/6 mice, plus the significant changes within their splenic ThI 7 and ThI cell populations,




the presence of circulating autoantibodies, specifically ANA, detectable by staining of HEp-2




cells was examined. To identify the presence of ANA, the sera prepared from blood samples




collected from each C57BL/6J mouse both pre- and post-cannulation were tested for reactivity




on HEp-2 cells. As presented in Figure 4A, the sera collected from C57BL/6J mice at 6 wks of




age or one wk prior to vector treatment showed a general weakly diffusedcytoplasmic and




nuclear background staining of the individual target cells. However, sera collected 19 wks post-




treatment from mice treated with Ad5-IL17A vector at 7 wks of age showed no cytoplasmic




staining with course speckled staining and negative nucleoli, while Ad5-LacZ treated mice




exhibited diffused cytoplasmic staining, weak but fine speckled nucleoplasmic staining with




negative nucleoli (Figures 4B & C). Similar results were seen in C7BL/6J mice whose salivary




glands were transduced with Ad5-IL17A vector at 16 wks of age in which the pattern was




pronounced course speckled staining with no cytoplasmic staining and negative nucleoli at 29




wks of age, or 11 wks post-treatment (Figures 4D-F). Considering the functions of IL-17A, it is




interesting to see a gradual and subtle change in ANA profile from diffused cytoplasmic/nuclear




13


pattern to a distinct course nuclear speckled pattern, suggesting influence of IL-17A on the B




cells repertoire.








Induction of salivary gland dysfunction in C57BL/6J mice following cannulation with




Ad5-1 LI7A vector




To determine if the expression of exogenous IL-17A can induce salivary gland dysfunction,




saliva volumes for each mouse were measured at 1 wk prior to treatment, then at 3-5 wk




intervals post-cannulation. C57BL/6J mice that received control Ad5-LacZ vector at 7 wks of




age exhibited stable stimulated saliva volumes at 7 wks post treatment with a statistically non-




significant increase in saliva volumes at 11 wks post treatment. Nevertheless, C57BL/6J mice




whose salivary glands were cannulated at 7 wks of age with Ad5-IL17A exhibited a significant




and relatively rapid decrease in stimulated saliva volumes that was most pronounced at 7 wks




post treatment, and this observation is seen even if the saliva volumes are converted to saliva




flow rates based on weights of the mice. After 7 wks post treatment, these mice showed a slight




recovery (Figure 5A). Similar results were observed with C57BL/6J mice cannulated at 16




wks of age with Ad5-LacZ and Ad5-IL17A vectors; however, no saliva volume recovery was




observed at time of euthanization (i.e., 11 wks post-treatment) (Figure 5B). Whether a reversal




of this inhibition would occur in these older animals will require further studies. Thus, saliva




secretions of mice receiving the Ad5-IL17A vector were significantly decreased 1-2 months




post-treatment when compared to secretions of mice receiving the Ad5-LacZ vector.
14


DISCUSSION




The THl7-derived IL-17A cytokine is a potent inflammatory cytokine that has been




implicated in a growing list of autoimmune diseases, e.g., multiple sclerosis, Crohn's disease,




rheumatoid arthritis, psoriasis, systemic lupus erythematosus, and SS, as well as autoimmunity




in animal models [3]. As the Th17/IL-17A system is considered to be an important factor in




innate immunity that, in turn, regulates development of the adaptive immune response, it is not




surprising that environmental microflora trigger IL-17A responses [34]. The consequence of




Th17/IL-17A activation includes, in addition to the production the IL-17A family of cytokines, the




production of IL-21, IL-22, chemokines (MIP-2, CXCL1, CXCL2, CXCL5), and matrix




metalloproteases (MMP3 and MMP13) [16] all actively involved in tissue inflammation.




Interaction of the IL-17A with its receptors evokes activation of IL-8, resulting in recruitment of




neutrophils to the site of injury. However, the relationship between such early




innate/inflammatory events mediated by the Th17/IL-17A system and the role Th17 cells play in




subsequent autoimmunity remains unknown, especially in light of the multiple functions now




associated with the ThI7 cell populations. Thus, in the present study, we have attempted to




elucidate the importance of the cytokine IL-17A perse in the development of SS and whether its




function may be dependent on when it is expressed.




Results in which SS-non-susceptible C57BL/6J mice were cannulated with the Ad5-




IL17A vector revealed that increased IL-17A expression could induce several pathological




features of SS, irrespective of whether the mice received the vector at 7 or 16 wks of age, two




time points corresponding to innate and adaptive immune responses in SS-susceptible




C57BL/6.NOD-/Aec'//Aec2 mice. This was noted by decreases in saliva production compared to




control vector, elevated production of specific pro-inflammatory cytokines detected in sera,




changes in the weak cytoplasmic/nuclear ANA patterns to nuclear specked staining on HEp2




cells and increased numbers of LF and IL17A positive cells present in the salivary glands at






15


time of euthanasia. Interestingly, mice received Ad5-IL17A at 7 wks of age showed a slight



recovery of saliva secretion at 7 wks of treatment in contrast to mice received Ad5-IL17A at 16



wks of age. This observation might be supported by the differential immunological or biological



response of mice at different ages and the effect of Ad5-IL17A exerted on the mice.



Previous studies have indicated that genes placed within Ad5 vectors are generally



expressed transiently and locally restricted (i.e., 7-14 days) [29]. The present study



demonstrates that a rapid and significant increase in the levels of plasma IL-17A was affected at



12 days post-cannulation by the Ad5-IL17A transgene vector. Interestingly, this systemic



increase in IL17 cytokine levels correlated with significant increases in splenic IL-17A secreting



CD4+T cells that persisted at least 19 wks for mice treated at 7 wks of age and 11 wks for mice



treated at 16 wks of age. These observations indicated that the Ad5 vector effect was longer



than anticipated. Whether this effect might be due to an indirect secondary effect of the Ad5-



IL17 vector is unknown. In addition, the systemic increase in IL17A production by local



treatment of Ad5-IL17A presented in this study is consistent with previous studies by Bruce



Baum's laboratory [35-38]. Adesanya et al. [39] has demonstrated that acinar cells can be



punctured by retrograde salivary gland cannulation at a certain vector dosage. The injured



acinar cells which have compromised mucosal barrier integrity allow for leakage of the vector



systemically. Further studies by Kagami et al. [37] and He et al. [40] provided evidence that



ductal cannulation of salivary glands can also have systemic effects due to the secretory nature



of the salivary glands which are well endowed with protein synthesis organelles and secretory



machinery.



Nevertheless, these observations are consistent with the concept that SS develops



along specific biological processes in a sequential fashion and interference with this process



alters development of disease [1-3]. Therefore, this study clearly indicates the pathogenic



nature of IL-17A in inducing SS-like phenotypes when cannulated in the salivary glands.
16


Previous data have shown that lymphocytic infiltrates in the salivary glands secreting IL-17A



and its related cytokines are more important in local glandular destruction. Staining salivary



glands for IL-17A revealed that C57BL/6J mice receiving Ad5-IL17A vector not only expressed



significant levels of IL-17A, but that IL-17A levels correlated with recruitment of inflammatory



cells, specifically B and T cells, to the glands. This observation is important in light of the recent



study suggesting IL-17A is a critical factor in the adaptive immune response by inducing the



formation of germinal centers for the production of autoreactive antibodies [24]. Autoantibodies



represent a major component in the onset of SS, thus the changes in the ANA profiles observed



with sera of C57BL/6J mice cannulated with the Ad5-IL17A vector indicate that IL-17A affects



even the B cell compartment in SS-non-susceptible mice. The presence of LF and loss of saliva



secretion raises an interesting question about the possible role of IL-17A in B cell activation. As



BAFF is capable of inducing ThI 7 cell differentiation in addition to regulating B cell activation



[41], the possible role of BAFF and IL17A in this phenomenon needs to be better defined in SS



pathogenesis.
17


CONCLUSIONS




The capability of IL-17A to induce features of SS in SS-non-susceptible mice demonstrates the




major role this cytokine plays in the development, and possibly onset, of the autoimmune




process. How this one cytokine affects the various features of autoimmunity, and at what level




or time point, will require additional studies. More importantly, the study demonstrates that IL-




17A might be a potential therapeutic target for SS.
18


LIST OF ABBREVATIONS




SS: Sjogren's Syndrome, IL: Interleukin, Ad5: Adenovirus serotype 5, IFN-y: Interferon-y, EAE:




Experimental autoimmune encephalomyelitis, CIA: Collagen-induced arthritis, LF: Lymphocytic




Focus, ANA: Antinuclear antibodies, MIP-2: Macrophage inflammatory protein-2, CXCL1:




Chemokine (C-X-C motif) ligand, MMP: matrix metalloproteases, BAFF: B cell activating factor.
19


COMPETING INTERESTS




The authors declare no conflicts of interest.


AUTHORS' CONTRIBUTIONS
JAC produced and determined the titers of the Ad5-LacZ and Ad5-IL17A viral vectors. HY and



BL performed retrograde ductal cannulations/instillations of the vectors into the salivary glands.



CQN designed the study, performed saliva flow, flow cytometry, histology and statistical



analyses, and prepared the manuscript. WC carried out the ANA staining. ABP assisted in the



manuscript preparation. All authors read and approved the final manuscript.
21


ACKNOWLEDGEMENTS




The authors would like to thank Dr. Jay K. Kolls and Dr. Julie Bindas (Children's Hospital of




Pittsburgh) for generously providing the Ad5-LacZ and Ad5-IL17A vectors and Dr. Phil Cohen




for his critical reading of the manuscript and helpful suggestions. We greatly appreciate the




assistance of Dr. Craig Meyers and Dr. Nicholas Muzyczka for the use of the microscope.




Publication of this article was funded in part by the University of Florida Open-Access publishing




Fund
22


FUNDING




This work was supported by PHS grants K99DE018958 (CQN) from NIDCR, R21AI081952




(ABP) from NIAID and funds from the Sjogren's Syndrome Foundation and Center for Orphan




Autoimmune Disorders. HY and JAC were supported by an NIH, NIDCR intramural research




grant.
23


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29


FIGURE LEGENDS:
Figure 1. Rapid changes in IL-17A and IL-6 serum cytokine concentrations in C57BL/6J



mice following vector cannulations. Sera were prepared from blood collected from individual



5 wk old mice (n=4) randomly chosen 1 wk prior to vector treatment (day 0 on the graph). Mice



were allowed to acclimate for 7 days, followed by vector instillation of each salivary gland with



50 |jl of vector solution containing 10'^ viral particles of either Ad5-LacZ or Ad5-IL17A vector.



Sera were again prepared from blood collected from individual mice (n=11) at day 5 and day 12



post-treatment. Concentrations of cytokines were determined using the Luminex platform. To



ensure sufficient quantities for testing, the sera of three individual mice of each experimental



group were pooled. ND: not detected indicates levels below threshold detection.








Figure 2. Intracellular staining for IL-17A and IFN-y secreting CD4'^T cells in spleens of



Ad5-IL17A-treated mice. Splenic leukocytes prepared from C57BL/6J mice (n=4) at 6 wks of



age (one wk prior to vector treatment) and 26 wks old (19 wks post vector treatment),



considered early treatment (A-C), or splenic leukocytes prepared from C57BL/6J mice (n=4) at



15 wks of age (one wk prior to vector treatment) and 27 wks old (11 wks post vector treatment),



considered late treatment (D-F) were examined for the presence of intracellular IL-17A and IFN-



Y gated on CD4'^T cells following a 5 hr in-vitro activation with anti-CD3£ and anti-CD28 in



Leukocyte Activation Cocktail containing GolgiPlug. Flow cytometric acquisition was performed



by staining with PE-Cy5-conjugated rat anti-CD4, FITC-conjugated rat anti-IFNy and/or PE-



conjugated rat anti-IL-17A. Data was analyzed by FCS Express. Flow cytometric images shown



are from one representative analysis of 2 independent experiments that examined 2 different



mice within each experiment. Data presented as mean + SEM for n=4 per group and statistical



analyses were performed comparing the means of the Ad-LacZ and Ad-IL17A treated groups at
30


26 wks and 27 wks of early and late treatment, respectively. (*) indicates p<0.5 using Mann-




Whitney U test.








Figure 3. Histological examination of salivary glands. Salivary gland histology was




examined at 19 wks post-vector infusions of mice treated at 7 wks of age (early treatment) or at




11 wks post-vector infusions of mice treated at 16 wks of age (late treatment). Panels show




representative H&E staining of salivary gland tissue from mice receiving early treatment with




Ad5-LacZ (n=10) (A), or Ad5-IL17A (n=11) (B); fluorescent staining and enumeration of B and T




cells in Ad5-IL17A treated mice (C & D) and immunohistochemical staining and enumeration of




IL-17A-positive cells in Ad5-IL17A treated mice (E & F); H&E staining of salivary gland tissue




from mice receiving late treatment with Ad5-LacZ (n=10) (G), or Ad5-IL17 (n=8) (H); and




fluorescent staining and enumeration of B and T cells in Ad5-IL17A treated mice (I & J) and




immunohistochemical staining and enumeration of IL-17A-positive cells in Ad5-IL17A treated




mice (K & L). Black arrows indicate representative lymphocytic infiltrate.








Figure 4. Identification of the antinuclear antibodies in sera of C57BL/6J mice.




Representative patterns of cellular staining of HEp-2 cells by sera diluted at 1:40 prepared from




sera taken from C57BL/6 mice cannulated with Ad5-LacZ or Ad5-IL17A vectors at 7 wks of age




with pre-treated mice (baseline) at 6 wks of age (n=4) (A-C), and cannulated at16 wks of age




with Ad5-LacZ or Ad5-IL17A and pre-treated mice (baseline) at 15 wks of age (n=4) (D-F) with




negative control using secondary antibody only (G) and positive control with standard nuclear




speckled serum (H). Representative patterns were determined with n=4 for two baselines and




n=7 for each time point presented in the figure. Fixed HEp-2 substrate slides were incubated




with individual mouse sera diluted 1:40, 1:80 and 1:160 followed by development with FITC-




conjugated goat anti-mouse IgG. Fluorescent patterns were detected by fluorescence




microscopy at 400X magnification.




31


Figure 5. Stimulated saliva flow in treated C57BL/6J mice. One week prior to salivary gland



cannulations with either Ad5-LacZ or Ad5-IL17A vector, stimulated saliva volumes were



determined for individual mice within each of the four experimental groups: early treatment with



Ad5-LacZ (n= 10) or Ad5-I LI 7A (n= 11) at 7 wks of age (A) or late treatment with Ad5-LacZ



(n=10) or Ad5-IL17A (n=8) at 16 wks of age (B). Saliva was collected every 3-5 wks post-



treatment until the mice were euthanized. Statistical analysis was used to determine the



significance between the Ad5-LacZ and Ad5-IL17A treated mice at each time point. (NS: not



significant, p=*<0.05, p=**<0.01, p=***<0.001). Arrows indicate the initial time point of vector



cannulation.
32


Table 1: Quantification of lymphocytic foci (LF) in salivary glands
Ad5:LacZ Ad5:IL17A
NoLF LF Mean LF NoLF LF Mean LF
Early 9^ (90%)'' 1 (10%) 1 1 (9%) 10(91%) 4 + 1.32"
Late 9 (90%) 1 (10%) 1 2 (25%) 6(75%) 2 + 0.83
^ number of mice
'percentage of mice
'^ mean number of LF + SEM per histological salivary gland section
LF; lymphocytic foci, Ad5; Adenovirus serotype 5, IL; interleukin.
33


IL-17 A
5000-1



4000-
- 3000-



Q. 2000-
1000-



0
^^day 0
Figure 1
IL-6
500-1



400
- 300.


OS
Q.200.
100<



0'
^UUS^JU^_
LE^
Iday5 ^3day 12
499999999999


Early treatment
A. 6 wks old mice (Pre-treatment) B. 26 wks old mice: Ad5-LacZ
iu : 1.520.21
10'- .
'"- '-'''. "
t ^ ii?^ -

in'^ ^tt ^jUB^.___~
PUft^^-^Pi,?:;;
B^^^^HI ^'. "-^ ?. ^ -'
m"- W^ >-^' 4.59+0.23.
C. 26 wks old mice: Ad5-IL17A
10 10 10 10
10"
10 10
Late treatment
D. 15 wks old mice (Pre-treatment) E. 27 wks old mice: Ad5-LacZ
F. 27 wks old mice: Ad5-IL17A
Figure 2


^Ad5-LacZ > ^^^^^ K^5-IL17A "J
C. Ad5:IL-17A
D.A 100i |.. g CD-'S S) 40-S 20-a. d5-IL17A
B220 CDS: Red Green Blue


CD3+ B22Q+


F. Ad5-IL17A
r-Kia/ ^i^
0 4 8 12 16 20
Percentage of cells per histological section
G. Ad5-I
Ad5-IL17A
Ts"*^ Ji f-- f' *'~

Figure 3
Ji.S4

) 10 15 20 25 30 35
Percentage of cells per histological section


Early treatment (cannulated at 7 wks old)
A. 6 wks old C57BL/6
Late treatment (cannulated at 16 wks old)
D. 15 wks old C57BL/6
B. Ad5-LacZ 26 wks
C. Ad5-L17A 26wks
E. AdS-LaczZ 29 wks
Controls
G. Negative control
H. Nuclear speckled control
F. Ad5-L17A 29 wks
!<;, '''. c" itV 1
>
z':*^ O" ft.
K ^i >
3 A
g* 9 1^ e "ci (
Figure 4


A. 7 weeks old mice cannulation
250
B. 16 weeks old mice cannulation
200
'^
"#-
-^ .
Week(s) post vector treatment
AdS-LacZ
-1 t 2 5 8
Week(s) post vector treatment

-Ad5-IL17A
Figure 5


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P7_ST00241
P7_SP00220 1173
P7_ST00242 1191
P7_SP00221 1212
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P7_SP00222 1335
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P7_SP00224 1638
P7_ST00246 240 microscope.
P7_SP00225
P7_ST00247
P7_SP00226
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P7_TL00023 2734
P7_ST00249 2742
P7_SP00227 2766
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P7_SP00228
P7_ST00251 601
P7_SP00229 679
P7_ST00252 695 AxioVs40
P7_SP00230 886
P7_ST00253 169 software
P7_SP00231 1072
P7_ST00254 (Ver.
P7_SP00232 1182 2775
P7_ST00255 147 4.7.1.0,
P7_SP00233 1347 2773
P7_ST00256 120 Zeiss)
P7_SP00234
P7_ST00257 (Carl
P7_SP00235 1598
P7_ST00258 Zeiss,
P7_SP00236 1732
P7_ST00259 1750 249 Thornwood,.
P7_TL00024 2840 1930
P7_ST00260 Enumeration
P7_SP00237 556 2872
P7_ST00261
P7_SP00238 612
P7_ST00262 628 B,
P7_SP00239 662 2879
P7_ST00263 26 T
P7_SP00240 707
P7_ST00264 722
P7_SP00241 810
P7_ST00265 827
P7_SP00242 898
P7_ST00266 915 total
P7_SP00243
P7_ST00267 1016 number
P7_SP00244 1169
P7_ST00268 1183 38
P7_SP00245 1221
P7_ST00269 1235 114 nuclei
P7_SP00246 1349
P7_ST00270 1368
P7_SP00247 1397
P7_ST00271
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P7_SP00249 1540
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P7_SP00250 1653
P7_ST00274 1671
P7_SP00251 1874 2881
P7_ST00275
P7_SP00252 1996
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P7_TL00025 2945 1069
P7_ST00277 imago
P7_SP00253 422 2986
P7_ST00278 440 168
P7_SP00254 608 2977
P7_ST00279 627 244 (Mayachitra,
P7_SP00255 871
P7_ST00280 893 65 Inc,
P7_SP00256 958 2984
P7_ST00281 977
P7_SP00257
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P2_SP00032 1322
P2_ST00036 1340 regarding
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P2_ST00037 1544 97 Th17 0.91 0003
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P2_SP00035 1722
P2_ST00039 1741 229 populations
P2_SP00036 1970
P2_ST00040 1986 75 that
P2_SP00037 2061 15
P2_ST00041 2076 680 146 secrete
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P2_ST00042 283 predominantly 0000000000000
P2_SP00038 586 825
P2_ST00043 604 202 interleukin
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P2_ST00044 161 (IL)-17A
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P2_ST00048 1374 785
P2_SP00044 1408
P2_ST00049 1427 79 play
P2_SP00045 1506
P2_ST00050 1522 792 46 an
P2_SP00046 1568
P2_ST00051 1587 important
P2_SP00047 1774
P2_ST00052 1791 role
P2_SP00048 1862
P2_ST00053 1880
P2_SP00049 1909
P2_ST00054 1927
P2_SP00050 1973
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P2_TL00006 890 1799
P2_ST00056 153 number
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P2_ST00057 470
P2_SP00052 508
P2_ST00058 521 248 autoimmune
P2_SP00053 769
P2_ST00059 786 diseases,
P2_SP00054 973 929
P2_ST00060 993 175 including
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P2_SP00056 1253
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P2_SP00057 1318
P2_ST00063 1335 61
P2_SP00058 1396
P2_ST00064 1414 891 149 40 present
P2_SP00059 1563
P2_ST00065 1579 115 study,
P2_SP00060 1694
P2_ST00066 1712 898 56 we
P2_SP00061 1768
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P2_SP00062
P2_ST00068 2042
P2_TL00007 995 1121
P2_ST00069 156 function
P2_SP00063 457 1027
P2_ST00070 475
P2_SP00064 513
P2_ST00071 528 130 IL-17A
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P2_ST00072 674 1003 45 on
P2_SP00066 719
P2_ST00073 737
P2_SP00067 797
P2_ST00074 814 development
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P2_ST00075 1089
P2_SP00069 1160
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P2_SP00070 1288
P2_ST00077 1303
P2_SP00071 1341
P2_ST00078 1354 68 SS,
P2_TL00008 1101 1900
P2_ST00079 194 Methods: 0.82 05000008
P2_SP00072 496 1133
P2_ST00080 514 227 Adenovirus
P2_SP00073 741
P2_ST00081 758 1102 171 serotype
P2_SP00074 1142
P2_ST00082 946 5
P2_SP00075 967
P2_ST00083 105 (Ad5)
P2_SP00076 1091
P2_ST00084 1109 144 vectors
P2_SP00077
P2_ST00085 1270 216 expressing
P2_SP00078 1486
P2_ST00086 1504 114 either
P2_SP00079 1618
P2_ST00087 129
P2_SP00080 1763
P2_ST00088 1780 or
P2_SP00081 1819
P2_ST00089 1835 96 LacZ
P2_SP00082 1931
P2_ST00090 1946 were
P2_SP00083
P2_ST00091 infused
P2_TL00009 1206 1928
P2_ST00092 55 via
P2_SP00084 356 1238
P2_ST00093 374 206 retrograde
P2_SP00085 580 1247
P2_ST00094 598 cannulation
P2_SP00086 827
P2_ST00095 846 into
P2_SP00087 914
P2_ST00096 930
P2_SP00088 991
P2_ST00097
P2_SP00089 1159
P2_ST00098 1176
P2_SP00090 1307
P2_ST00099 1324
P2_SP00091 1361
P2_ST00100 1375 195 C57BL6J 00000400
P2_SP00092 1570
P2_ST00101 1590 91 mice
P2_SP00093 1681
P2_ST00102 1699 between
P2_SP00094 1866
P2_ST00103 1883 63 6-8
P2_SP00095
P2_ST00104 1961 128 weeks
P2_SP00096 2089
P2_ST00105 2106
P2_SP00097 2143
P2_ST00106 2157 1214 72 age
P2_TL00010 1311 1662
P2_ST00107 1319
P2_SP00098 341 1343
P2_ST00108
P2_SP00099 523
P2_ST00109 544 110 15-17
P2_SP00100 654
P2_ST00110 669
P2_SP00101
P2_ST00111
P2_SP00102 852
P2_ST00112 865 83 age.
P2_SP00103 948 1352
P2_ST00113 979 The
P2_SP00104 1054
P2_ST00114 1072 92
P2_SP00105 1164
P2_ST00115
P2_SP00106 1276
P2_ST00116 1293 270 characterized
P2_SP00107
P2_ST00117 1580 124 forSS
P2_SP00108 1704
P2_ST00118 242 phenotypes.
P2_TL00011 1417 1858
P2_ST00119 172 Results: 0.83
P2_SP00109 474 1449
P2_ST00120 495 159 Disease
P2_SP00110
P2_ST00121 672 profiling
P2_SP00111 826 1458
P2_ST00122 177 indicated
P2_SP00112 1023
P2_ST00123 1040
P2_SP00113 1115
P2_ST00124 1130 393 SS-non-susceptible 000000000000000000
P2_SP00114 1523
P2_ST00125 1540
P2_SP00115 1735
P2_ST00126 1755
P2_SP00116 1846
P2_ST00127 whose
P2_SP00117
P2_ST00128 2009
P2_TL00012
P2_ST00129
P2_SP00118 433
P2_ST00130 451 received
P2_SP00119 618 1554
P2_ST00131 635
P2_SP00120 695
P2_ST00132 710 215 Ad5-IL17A
P2_SP00121 925
P2_ST00133 941 vector
P2_SP00122 1065
P2_ST00134 1079 developed
P2_SP00123 1285
P2_ST00135 1530
P2_SP00124
P2_ST00136 1342 140 SS-like
P2_SP00125 1482
P2_ST00137 disease
P2_SP00126 1653
P2_ST00138 1671 profile,
P2_SP00127 1801
P2_ST00139 1822 174
P2_TL00013 1628 1831
P2_ST00140 1636 appearance
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P2_ST00141 557
P2_SP00129 594 1660
P2_ST00142 609 236 lymphocytic
P2_SP00130 845
P2_ST00143 859 78 foci,
P2_SP00131 937 1667
P2_ST00144 192 increased
P2_SP00132
P2_ST00145 164 cytokine
P2_SP00133 1332
P2_ST00146 1350 122 levels,
P2_SP00134 1472
P2_ST00147 1492 169 changes
P2_SP00135 1661
P2_ST00148 1679
P2_SP00136 1708
P2_ST00149 1726 223 antinuclear
P2_SP00137 1949
P2_ST00150 1963 170 antibody
P2_TL00014 1733 815
P2_ST00151 profiles,
P2_SP00138
P2_ST00152
P2_SP00139 546 1765
P2_ST00153 563 temporal
P2_SP00140 738
P2_ST00154 756 77 loss
P2_SP00141 833
P2_ST00155 850
P2_SP00142 887
P2_ST00156 901 112
P2_SP00143 1013
P2_ST00157 1030 88 flow.
P2_TL00015 1838
P2_ST00158 279 Conclusions: 0.92 000000000008
P2_SP00144 583 1870
P2_ST00159 617 179 Induction
P2_SP00145 796
P2_ST00160
P2_SP00146
P2_ST00161 57 SS 0.98
P2_SP00147
P2_ST00162 940 pathology
P2_SP00148 1134 1879
P2_ST00163 1151 by
P2_SP00149 1195
P2_ST00164
P2_SP00150
P2_ST00165 1360
P2_SP00151 1389
P2_ST00166
P2_SP00152
P2_ST00167
P2_SP00153
P2_ST00168 157 strongly
P2_TL00016 1944 1922
P2_ST00169 1945 180 suggests
P2_SP00154 482 1985
P2_ST00170 497
P2_SP00155 572 1976
P2_ST00171
P2_SP00156
P2_ST00172 736 28 is
P2_SP00157 764
P2_ST00173 781 1952
P2_SP00158
P2_ST00174 000001000
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P2_ST00175 1050 257 inflammatory
P2_SP00160
P2_ST00176 163
P2_SP00161 1487
P2_ST00177
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P2_SP00163 1705
P2_ST00179 1721 107 gland
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P2_ST00180 dysfunction.
P2_SP00165 2084
P2_ST00181 2115 Thus,
P2_TL00017 2049 1608
P2_ST00182 localized
P2_SP00166 2081
P2_ST00183 493 anti-IL17
P2_SP00167
P2_ST00184 683 150 therapy
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P2_ST00186 950 be
P2_SP00170
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P2_SP00171
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P2_SP00172 1227
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P12_SP00070
P12_ST00077 1937 number
P12_SP00071 2090 9
P12_ST00078 2099
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P12_ST00081
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P12_ST00082 515
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P12_ST00084 761
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P12_ST00089 1352 97 often
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P12_ST00090 1467 174 correlate
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P12_ST00091 1658 141 directly
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P12_ST00092 1814 78
P12_SP00085 1892
P12_ST00093 1910
P12_SP00086 2064
P12_ST00094 2081 1161 or
P12_SP00087 2120
P12_ST00095 2135 its
P12_TL00008 1899
P12_ST00096 164 severity,
P12_SP00088 466 1300
P12_ST00097 485
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P12_ST00098 560 156 patients
P12_SP00090 716
P12_ST00099
P12_SP00091 804
P12_ST00100 824 NOD-derived
P12_SP00092
P12_ST00101 1103 1267 mouse
P12_SP00093 1235
P12_ST00102 1252 strains
P12_SP00094 1383
P12_ST00103 1400 188 exhibiting
P12_SP00095 1588
P12_ST00104 1602 140 SS-like
P12_SP00096 1742
P12_ST00105 1760
P12_SP00097 1913
P12_ST00106 1929 161 typically
P12_SP00098
P12_ST00107 2107 94 have
P12_TL00009 1364 1777
P12_ST00108 237 lymphocytic
P12_SP00099 540 1405
P12_ST00109 555 infiltrates
P12_SP00100 734 1396
P12_ST00110 751
P12_SP00101
P12_ST00111 798 250 theirsalivary 0000000000000
P12_SP00102
P12_ST00112 glands.
P12_SP00103 1205 25
P12_ST00113 1230 IL-17A
P12_SP00104 1360
P12_ST00114 1376 1372 appears
P12_SP00105
P12_ST00115 1553 1365 to
P12_SP00106
P12_ST00116 1606 79 play
P12_SP00107 1685
P12_ST00117 1702
P12_SP00108
P12_ST00118 1740
P12_SP00109 1865
P12_ST00119 1884 role
P12_SP00110 1955
P12_ST00120 1973
P12_SP00111 2002
P12_ST00121 2019
P12_TL00010 1469
P12_ST00122
P12_SP00112 1510
P12_ST00123 577
P12_SP00113 615 1501
P12_ST00124
P12_SP00114
P12_ST00125 694
P12_SP00115
P12_ST00126 785 69 has
P12_SP00116 854
P12_ST00127 871 recently
P12_SP00117 1027
P12_ST00128 1045 been
P12_SP00118 1140
P12_ST00129 1157 110 found
P12_SP00119
P12_ST00130 1285 1470 34
P12_SP00120 1319
P12_ST00131 1338 be
P12_SP00121
P12_ST00132 1401
P12_SP00122 1550
P12_ST00133 1564 114 within
P12_SP00123 1678
P12_ST00134 1698
P12_SP00124 1744
P12_ST00135 1763
P12_SP00125 1792
P12_ST00136 1812
P12_SP00126
P12_ST00137 1912
P12_SP00127 1969
P12_ST00138 1987
P12_SP00128 2143
P12_ST00139 2160
P12_TL00011 1575
P12_ST00140
P12_SP00129 432
P12_ST00141 451 143 models
P12_SP00130 594
P12_ST00142 611 56 [8].
P12_SP00131 667 1616
P12_ST00143 699 160 Salivary
P12_SP00132 859
P12_ST00144 875
P12_SP00133 1006
P12_ST00145 1023
P12_SP00134 1061
P12_ST00146 1074 196 C57BL6J 00000400
P12_SP00135 1270
P12_ST00147 1289 92
P12_SP00136 1381
P12_ST00148
P12_SP00137 1571
P12_ST00149 1589 229 cannulation
P12_SP00138 1818
P12_ST00150 1834
P12_SP00139
P12_ST00151 1928 215
P12_TL00012 1680 1922
P12_ST00152 1681
P12_SP00140 426 1712
P12_ST00153 438 1688 were
P12_SP00141 534
P12_ST00154 552 193 examined
P12_SP00142
P12_ST00155 762 53
P12_SP00143 815
P12_ST00156 828
P12_SP00144 889
P12_ST00157 907 183 presence
P12_SP00145 1090 1721
P12_ST00158 1107
P12_SP00146 1145
P12_ST00159 1159 infiltrating
P12_SP00147 1349
P12_ST00160 1368 222 leukocytes.
P12_SP00148
P12_ST00161 1622 159
P12_SP00149 1781
P12_ST00162 1798
P12_SP00150
P12_ST00163 1946 172 retrieved
P12_SP00151 2118
P12_ST00164 88 from
P12_TL00013 1786 1900
P12_ST00165 195
P12_SP00152
P12_ST00166 517 91
P12_SP00153 608
P12_ST00167 625 138 treated
P12_SP00154 763
P12_ST00168 779
P12_SP00155 857
P12_ST00169 873 197 Ad5-LacZ
P12_SP00156 1070
P12_ST00170 1086 1787 124
P12_SP00157
P12_ST00171 1224 36
P12_SP00158 1260
P12_ST00172 1275 either
P12_SP00159 1389
P12_ST00173 1402 7
P12_SP00160 1423
P12_ST00174 1441 1794
P12_SP00161 1480
P12_ST00175 1497 44
P12_SP00162 1541
P12_ST00176 1556
P12_SP00163 1633
P12_ST00177 1650
P12_SP00164 1687
P12_ST00178 1701 age
P12_SP00165 1773 1827
P12_ST00179 1791 169 revealed
P12_SP00166 1960
P12_ST00180 1977
P12_SP00167 2052
P12_ST00181 2070 83 10%
P12_SP00168 2153
P12_ST00182 2173 (1
P12_TL00014 1891 1927
P12_ST00183
P12_SP00169 1923
P12_ST00184 356 10)
P12_SP00170 414 1932
P12_ST00185 433
P12_SP00171 462
P12_ST00186 each
P12_SP00172 574
P12_ST00187 113 group
P12_SP00173 705
P12_ST00188 723 70 had
P12_SP00174 793
P12_ST00189 812 evidence
P12_SP00175 991
P12_ST00190 1008
P12_SP00176 27
P12_ST00191 1072 glandular
P12_SP00177
P12_ST00192 1274 214 infiltrations
P12_SP00178 1488
P12_ST00193 (Figure
P12_SP00179 1655
P12_ST00194 65 3A,
P12_SP00180 1738 1930
P12_ST00195 1758 B,
P12_SP00181 1797
P12_ST00196 1815 43 G,
P12_SP00182
P12_ST00197 1878 H,
P12_SP00183 1917
P12_ST00198 1935 115 Table
P12_SP00184 2050
P12_ST00199 1).
P12_SP00185 2114
P12_ST00200 2145 84 This
P12_TL00015 1840
P12_ST00201 232 observation
P12_SP00186 2029
P12_ST00202
P12_SP00187 581
P12_ST00203 598 203 consistent
P12_SP00188 801
P12_ST00204
P12_SP00189 893
P12_ST00205 910
P12_SP00190 970
P12_ST00206 988
P12_SP00191 1141
P12_ST00207 1156
P12_SP00192 1193
P12_ST00208 1207 healthy,
P12_SP00193 2038
P12_ST00209 untreated
P12_SP00194 1568
P12_ST00210 1586
P12_SP00195
P12_ST00211 1801
P12_SP00196
P12_ST00212 180 expected
P12_SP00197
P12_ST00213 2108 1998
P12_TL00016 2102 1819
P12_ST00214
P12_SP00198 397 2134
P12_ST00215
P12_SP00199 605
P12_ST00216 623
P12_SP00200 661
P12_ST00217 673
P12_SP00201
P12_ST00218 750
P12_SP00202 902
P12_ST00219 919
P12_SP00203
P12_ST00220 1067
P12_SP00204 1123
P12_ST00221 1158 In
P12_SP00205 1188
P12_ST00222 2103 contrast,
P12_SP00206 2141
P12_ST00223 1395
P12_SP00207 1547
P12_ST00224 1563
P12_SP00208 1694
P12_ST00225
P12_SP00209
P12_ST00226 1816
P12_SP00210 2011
P12_ST00227 2031
P12_TL00017 2207 1856
P12_ST00228
P12_SP00211 439 2239
P12_ST00229
P12_SP00212
P12_ST00230 550
P12_SP00213
P12_ST00231 780 2208
P12_SP00214 905
P12_ST00232
P12_SP00215 954
P12_ST00233 969
P12_SP00216 990
P12_ST00234
P12_SP00217 1083
P12_ST00235 1099
P12_SP00218 1137
P12_ST00236 1150 2215
P12_SP00219 1222 2248
P12_ST00237 1240 showed
P12_SP00220 1392
P12_ST00238 1411
P12_SP00221 1625
P12_ST00239 1643
P12_SP00222 1672
P12_ST00240 1690 86 91%
P12_SP00223 1776
P12_ST00241 1796 (10
P12_SP00224 1857
P12_ST00242 1874
P12_SP00225 1911
P12_ST00243 11)
P12_SP00226 1986
P12_ST00244
P12_SP00227 2080
P12_ST00245 2097
P12_TL00018 2313
P12_ST00246 2321 108 mean
P12_SP00228 411 2345
P12_ST00247 431
P12_SP00229 478
P12_ST00248 64 per
P12_SP00230 561 2354
P12_ST00249 220 histological
P12_SP00231 796
P12_ST00250 814 section
P12_SP00232
P12_ST00251 973 numbering
P12_SP00233 1183
P12_ST00252 1200 22 4
P12_SP00234
P12_ST00253 2318 +
P12_SP00235 1262 2340
P12_ST00254 1282 1.32,
P12_SP00236 1374 2352
P12_ST00255 while
P12_SP00237 1494
P12_ST00256 1511
P12_SP00238 1662
P12_ST00257 1679
P12_SP00239 1810
P12_ST00258 1826
P12_SP00240
P12_ST00259 1931
P12_SP00241 2127
P12_ST00260
P12_TL00019 2418
P12_ST00261
P12_SP00242 2450
P12_ST00262
P12_SP00243
P12_ST00263
P12_SP00244
P12_ST00264 2419
P12_SP00245
P12_ST00265
P12_SP00246
P12_ST00266 972
P12_SP00247 1016
P12_ST00267 1031
P12_SP00248 1108
P12_ST00268 1125
P12_SP00249 1162
P12_ST00269 1176 2426
P12_SP00250 1248 2459
P12_ST00270 1266
P12_SP00251 1435
P12_ST00271 1455
P12_SP00252 1669
P12_ST00272 1686
P12_SP00253 1716
P12_ST00273 1734 75%
P12_SP00254 1820
P12_ST00274 1839 (6
P12_SP00255
P12_ST00275
P12_SP00256
P12_ST00276 1943 8)
P12_SP00257
P12_ST00277 1994
P12_SP00258 2072
P12_ST00278
P12_SP00259 2111
P12_ST00279 2130
P12_TL00020 2524 1134
P12_ST00280
P12_SP00260 350 2556
P12_ST00281 369
P12_SP00261
P12_ST00282 537 2532
P12_SP00262 601 2565
P12_ST00283 616 221
P12_SP00263 837
P12_ST00284 855
P12_SP00264 995
P12_ST00285 1013
P12_SP00265
P12_ST00286 1063 2
P12_SP00266
P12_ST00287 1102 2529
P12_SP00267 1124 2551
P12_ST00288 85 0.83
P12_SP00268 1226
P12_ST00289 1244 (Table
P12_SP00269
P12_ST00290 1393
P12_TL00021 454 2629
P12_ST00291 Besides
P12_SP00270 2661
P12_ST00292 627
P12_SP00271 687
P12_ST00293
P12_SP00272 858
P12_ST00294 872
P12_SP00273
P12_ST00295 925
P12_SP00274
P12_ST00296 170 detected
P12_SP00275 1160
P12_ST00297 1179
P12_SP00276 1208
P12_ST00298
P12_SP00277 1286
P12_ST00299 1303
P12_SP00278 2670
P12_ST00300 1471
P12_SP00279
P12_ST00301 1619
P12_SP00280
P12_ST00302
P12_SP00281 1729
P12_ST00303 1746 258 experimental
P12_SP00282 2004
P12_ST00304 2022 animals,
P12_TL00022 2734 1875
P12_ST00305 384 immunofluorescent 00000000000000000
P12_SP00283 2766
P12_ST00306 702 staining
P12_SP00284 2775
P12_ST00307 2735
P12_SP00285 906
P12_ST00308 924 122 detect
P12_SP00286
P12_ST00309 B
P12_SP00287 1087
P12_ST00310 1105
P12_SP00288
P12_ST00311 26 T
P12_SP00289 1219
P12_ST00312 1234 cells
P12_SP00290 1322
P12_ST00313 1340
P12_SP00291 1509
P12_ST00314 1527 further 0001000
P12_SP00292 1659
P12_ST00315 differences
P12_SP00293 1893
P12_ST00316
P12_SP00294 1940
P12_ST00317 1957
P12_SP00295 2017
P12_ST00318 2034 144 cellular
P12_TL00023 2840 1902
P12_ST00319 239 composition
P12_SP00296 541 2881
P12_ST00320 559
P12_SP00297 597 2872
P12_ST00321 609
P12_SP00298 670
P12_ST00322 688
P12_SP00299
P12_ST00323 920 166 between
P12_SP00300
P12_ST00324 1106
P12_SP00301 1197
P12_ST00325 1214 257 administered
P12_SP00302
P12_ST00326 1487
P12_SP00303
P12_ST00327 1719 2841
P12_SP00304 1754
P12_ST00328 1770 2848 an
P12_SP00305
P12_ST00329 1833 early
P12_SP00306
P12_ST00330 1945
P12_SP00307 1985
P12_ST00331 2000 68 late
P12_SP00308
P12_ST00332 stage.
P12_TL00024 300 2945
P12_ST00333 At
P12_SP00309 343 2977
P12_ST00334 357 time
P12_SP00310 440
P12_ST00335 457
P12_SP00311 495
P12_ST00336 508 231 euthanasia,
P12_SP00312 739 2984
P12_ST00337 758
P12_SP00313
P12_ST00338
P12_SP00314
P12_ST00339 1081
P12_SP00315
P12_ST00340
P12_SP00316 1313
P12_ST00341 1329
P12_SP00317 1544
P12_ST00342 1560 2946
P12_SP00318 1684
P12_ST00343
P12_SP00319
P12_ST00344 1749
P12_SP00320
P12_ST00345 1785
P12_SP00321 1862
P12_ST00346 1879
P12_SP00322
P12_ST00347 2953
P12_SP00323 2986
P12_ST00348 182 generally
P12_TL00025 3053
P12_ST00349


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P32_SP00002 487 447 31
P32_ST00003 518 229 Stimulated 0000000000
P32_SP00003 747 17
P32_ST00004 764 124 saliva
P32_SP00004
P32_ST00005 904 91 flow 0000
P32_SP00005 995
P32_ST00006 1011 34 in
P32_SP00006 1045
P32_ST00007 1062 148 treated 0000000
P32_SP00007 1210 19
P32_ST00008 1229 204 C57BL6J 0.90 00000800
P32_SP00008 1433
P32_ST00009 1452 109 mice. 00000
P32_SP00009 1561
P32_ST00010 1593 83 One 000
P32_SP00010 1676 15
P32_ST00011 1691 106 week
P32_SP00011 1797
P32_ST00012 1813 90 prior
P32_SP00012 1903 13
P32_ST00013 1916 416 35 to
P32_SP00013 1951
P32_ST00014 1968 151 salivary 00000000
P32_SP00014 2119
P32_ST00015 2136 107 gland
P32_TL00002 302 521 1766 39
P32_ST00016 253 cannulations 000000000000
P32_SP00015 555 553
P32_ST00017 570 78 with
P32_SP00016 648 18
P32_ST00018 666 114 either
P32_SP00017 780 12
P32_ST00019 792 196 Ad5-LacZ
P32_SP00018 988
P32_ST00020 1005 529 40 24 or
P32_SP00019
P32_ST00021 1057 215 Ad5-IL17A 000000000
P32_SP00020 1272
P32_ST00022 1287 522 132 38 vector,
P32_SP00021 1419 560
P32_ST00023 1438 stimulated
P32_SP00022 1642
P32_ST00024 1660 113
P32_SP00023 1773
P32_ST00025 1789 168 volumes
P32_SP00024 1957 14
P32_ST00026 1971 97 were
P32_TL00003 626 1931
P32_ST00027 224 determined
P32_SP00025 526 658
P32_ST00028 543 53 for
P32_SP00026 596
P32_ST00029 611 185 individual
P32_SP00027 796
P32_ST00030 815 92 mice
P32_SP00028 907
P32_ST00031 922 within
P32_SP00029 1035
P32_ST00032 1054 94 each
P32_SP00030 1148
P32_ST00033 1166 37 of
P32_SP00031 1203
P32_ST00034 1216 60 the
P32_SP00032 1276
P32_ST00035 1292 79 four
P32_SP00033 1371
P32_ST00036 1385 257 experimental
P32_SP00034 667
P32_ST00037 634 146 groups:
P32_SP00035 1806
P32_ST00038 1839 95 early
P32_SP00036 1934
P32_ST00039 1950 627 192 treatment
P32_SP00037 2142
P32_ST00040 2155
P32_TL00004 300 732 1822
P32_ST00041 197
P32_SP00038 497
P32_ST00042 514 61 (n
P32_SP00039 575 773 9
P32_ST00043 584 1
P32_SP00040 10
P32_ST00044 606 36 0)
P32_SP00041 642
P32_ST00045 660 740
P32_SP00042 699
P32_ST00046 711 105 Ad5-I
P32_SP00043 816
P32_ST00047 825 LI
P32_SP00044 863 11
P32_ST00048 874 7A
P32_SP00045 927
P32_ST00049 944
P32_SP00046 1004
P32_ST00050 1013
P32_SP00047 1025
P32_ST00051 1039
P32_SP00048 1051
P32_ST00052 1060 )
P32_SP00049 1071
P32_ST00053 1089 733 at
P32_SP00050 1125
P32_ST00054 1140 21 7
P32_SP00051 1161
P32_ST00055 1176 77 wks
P32_SP00052 1253
P32_ST00056 1270
P32_SP00053 1308
P32_ST00057 1321 72 age
P32_SP00054 1393
P32_ST00058 1411 58 (A)
P32_SP00055 1469
P32_ST00059 1487
P32_SP00056 1526
P32_ST00060 1541 69 late
P32_SP00057 1610
P32_ST00061 1626
P32_SP00058 1818
P32_ST00062 1831
P32_SP00059 1909
P32_ST00063 1925
P32_TL00005 837 1816
P32_ST00064 127 10)
P32_SP00060 430 878
P32_ST00065 448 845
P32_SP00061 488 869
P32_ST00066 500
P32_SP00062 715
P32_ST00067 102 8)
P32_SP00063 834
P32_ST00068 852 838
P32_SP00064
P32_ST00069 906 44
P32_SP00065 950
P32_ST00070 965
P32_SP00066 1042
P32_ST00071 1059
P32_SP00067 1096
P32_ST00072 1110
P32_SP00068 1182
P32_ST00073 1200 68 (B).
P32_SP00069 1268
P32_ST00074 1301 120 Saliva
P32_SP00070 1421
P32_ST00075 1436 80 was
P32_SP00071 1516
P32_ST00076 1532 176 collected
P32_SP00072 1708
P32_ST00077 1726 108 every
P32_SP00073 1834
P32_ST00078 1851 62 3-5
P32_SP00074 1913
P32_ST00079 1928
P32_SP00075 2005
P32_ST00080 2023 96 post-
P32_TL00006 942 1785
P32_ST00081 943
P32_SP00076 493 974
P32_ST00082 509 until
P32_SP00077 587
P32_ST00083 604
P32_SP00078 665
P32_ST00084 683
P32_SP00079 774
P32_ST00085 789
P32_SP00080 886
P32_ST00086 903 231 euthanized. 00000000000
P32_SP00081 1134
P32_ST00087 191 Statistical
P32_SP00082 1357
P32_ST00088 1375 161 analysis
P32_SP00083 1536 983
P32_ST00089 1551
P32_SP00084 1631
P32_ST00090 1648 93 used
P32_SP00085 1741
P32_ST00091 1758
P32_SP00086 1793
P32_ST00092 1810 200 determine
P32_SP00087 2010
P32_ST00093 2026
P32_TL00007 1048 1875
P32_ST00094 235 significance
P32_SP00088 537
P32_ST00095 167 between
P32_SP00089 722 1080
P32_ST00096 739
P32_SP00090 799
P32_ST00097
P32_SP00091
P32_ST00098 1028 71 and
P32_SP00092 1099
P32_ST00099 1115
P32_SP00093 1330
P32_ST00100 1346 138
P32_SP00094 1484
P32_ST00101 1503
P32_SP00095 1594
P32_ST00102 1612 1049
P32_SP00096 1647
P32_ST00103 1663
P32_SP00097 1757
P32_ST00104 1774 time
P32_SP00098 1857
P32_ST00105 point.
P32_SP00099 1980
P32_ST00106 2013 84 (NS:
P32_SP00100 2097 20
P32_ST00107 2117 not
P32_TL00008 1153 1877
P32_ST00108 210 significant,
P32_SP00101 512 1194
P32_ST00109 532 p *<0.05,
P32_SP00102 723
P32_ST00110 744 **<0.01
P32_SP00103 936
P32_ST00111 949 1181 4 ,
P32_SP00104 953 1192
P32_ST00112 973 268 ***<0.001). 0000000000000
P32_SP00105 1241 30
P32_ST00113 1271 141 Arrows
P32_SP00106 1412 1185
P32_ST00114 1429 153 indicate
P32_SP00107 1582
P32_ST00115 1598
P32_SP00108 1658
P32_ST00116 99 initial
P32_SP00109 1775
P32_ST00117 1792
P32_SP00110
P32_ST00118 1893 point
P32_SP00111 1989
P32_ST00119 2004
P32_SP00112 2042
P32_ST00120 2054 1154 125 vector
P32_TL00009 1259 240
P32_ST00121 cannulation.
P32_TB00002 1248 3047 54 42
P32_TL00010 1254 3053
P32_ST00122 0.97



PAGE 1

1 Pathogenic effect of interleukin 17A in induction of Sjšgren's s yndrome like disease using adenovirus mediated gene transfer Cuong Q. Nguyen 1,2 ,3,4 Hongen Yin 5 Byung Ha Lee 3 Wendy C. Carcamo 3 J ohn A. Chiorini 5 & Ammon B. Peck 3,4,6 1 Eli and Ed ythe L. Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA 2 Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave, E25 545, Cambridge MA 02139, USA 3 Department of Oral Biology, University of Florida Co llege of Dentistry, 1600 SW Archer Rd, Gainesville, Florida 32610, USA 4 Center for Orphan Autoimmune Disorders, University of Florida College of Dentistry, 1600 SW Archer Rd, Gainesville, Florida 32610 USA 5 National Institute of Dental and Craniofacia l Research, NIH, 10 Center Drive MSC 1190, Bethesda, Maryland 20892 USA 6 Department of Pathology, Immunology & Laboratory Medicine, University of Florida College of Medicine, 1600 SW Archer Rd, Gainesville, Florida 32610 USA Running title: The role o f IL 17A in Sjšgren's Syndrome Address c orrespondence : Cuong Q. Nguyen, PhD Department of Oral Biology PO Box 100424, College of Dentistry University of Florida Gainesville, Florida 32610 USA Telephone: 352 273 8865 FAX: 352 273 882 9 E mail: Nguyen@pathology.ufl.edu

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2 A BSTRACT : Introduction : Sjšgren's syndrome (SS) involves a chronic, progressive inflammation primarily of the salivary and lacrimal glands leading to decreased levels of saliva and tears resulting in dry mouth and dry eye diseases. Seminal findings regarding T H 17 cell population s that secrete predominantly interleukin ( IL ) 17 A ha ve been shown to play an important role in an increasing number of autoimmune diseases, in cluding SS In the present study, we investigated the function of IL 17A on the development and onset of SS Methods : A denovirus serotype 5 (Ad5) vectors expressing either IL 17A or LacZ were infused via retrograde cannulation into the salivary glands of C57BL/6J mice between 6 8 w ee ks of age or between 15 17 w ee ks of age. The mice were characterized for SS phenotypes. Results : D isease profiling indicated that SS non susceptible C57BL/6J mice whose salivary glands received the Ad5 IL17A vector develope d a SS like disease profile, including appearance of lymphocytic foci, increased cytokine levels changes in antinuclear antibody profiles, and temporal loss of saliva flow Conclusions : Induction of SS pathology by IL 17A in SS non susceptible mice s trongly suggest s that IL 17A is an important inflammatory cytokine in salivary gland dysfunction. Thus, localized anti IL17 therapy may be effective in preventing glandular dysfunction

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3 INTRODUCTION Sjšgren's syndrome ( SS ) is a chronic, systemic autoim mune disease characterized most notably by development of dry eyes and dry mouth manifestations, indicative of secretory dysfunction of the lacrimal and salivary glands [1 3] Although the etiology of SS remains un known, intensive studies of an ever expanding number of animal models is beginning to unravel the genetic, molecular and immunological basis for this disease [1] Previous studies have implicated critical roles for both interferon ( IFN ) and interleukin ( IL ) 4 in development and onset of SS like disease in NOD/LtJ and C57BL/6.NOD Aec1Aec2 mice [4, 5] strongly suggesting involvement of T H 1 and T H 2 cell populations, respectively. While IFN regulates cell mediated immunity through activation of macrophages, NK cells and CD8 + T cells, this cytokine appears to predispose these SS susceptible mice by retarding salivary gland organogenesis, especially proliferation of acinar tissue [5] This delay in acinar c ell maturation has been postulated to prevent expression of cellular antigens at the critical time of self tolerance, resulting in inefficient clonal deletion of acinar tissue reactive T cells. In contrast to the role of IFN both prior to and during dev elopment of SS IL 4 appears to be essential during development of adaptive immunity and subsequent onset of glandular dysfunction. Specifically, IL 4 was shown to be necessary for proper isotypic switching, regulating B lymphocyte synthesis of pathogenic IgG1 anti muscarinic acetylcholine type III receptor (M3R) autoantibodies [6, 7] Although these earlier studies have implicated both T H 1 and T H 2 cell associated functions in the development and onset of clinica l SS recent identification of the CD4 + T H 17 memory cells within the lymphocytic focus (LF) of lacrimal and salivary glands of SS s C57BL/6.NOD Aec1Aec2 mice, as well as minor salivary glands of human SS patients, greatly expands the potential complexity in deciphering the autoimmune response underlying SS [8, 9] The T H 17 cell population, while clearly a subset of CD4 + memory effector T cells, appears to be

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4 distinct from, and unrelated to, either the T H 1 or T H 2 cell lineages [10 14] T H 17 effector cells secrete at least one of the six cytokines belonging to the IL 17 family, i.e., IL 17 A, IL 17 B, IL 17 C, IL 17 D, IL 25 and/or IL 17 F ; however, IL 17 A the signature cytokine, ha s received the greatest attention in studies of autoimmune diseases [15] The IL17 cytokines are potent pro inflammatory molecules, actively involved in tissue in flammation via induction of pro inflammatory cytoki ne and chemokine expressions [16] In addition, IL 17 is involved in the mobilization, maturation and migration of neutrophils via the release of IL 8 at the site of injury [17] Interestingly, IL 17A is known to regulate Foxp3+ T Reg cells and vice versa [18] While T H 17 cells have been implicat ed in several autoimmune diseases (e.g., Crohn's disease [19, 20] experimental autoimmune encephalomyelitis (EAE) [21] collagen induced arthritis CIA) [21] SS [8] and others [2, 3] ), this characteristic may require signaling from T H 1 cells already present in the lesion [3] In any event, recent observational studies in SS patients and animal models of primary SS have identified the presence of IL 17 A and its activating cytokine IL 23 in the lymphocytic infiltrates of the exocrine glands, as well as higher levels of circulating IL 1 7 A in both sera and saliva [8] raising the question of the importance of IL 17 in SS Thus, the goals of the present study were to determine whether IL 17A can directly influence the pathology leading to the onset of SS like diseas e by administrati ng exogenous IL 17A to the salivary glands at specific time points

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5 MATERIALS AND METHODS Animals SS non susceptible C57BL/6J mice were bred and maintained under specific pathogen free conditions. The animals were maintained on a 12 hr light dark schedule and provided food and acidified water ad libitum At times indicated in the text, mice were euthanized by cervical dislocation following deep anesthetization with isoflurane, after which organs were freshly explanted for analyses. Bo th the breeding and use of these animals for the present studies were approved by the University of Florida's IACUC and IBC. Sali vary glands of mice were cannulated with mouse IL 17A expressing Ad5 IL17A vector using retrograde injections at either 7 week s ( wks ) of age (n=11) or 16 wks of age (n=8). In addition, mice at 6 wks (n=4) and 15 wks (n=4) were randomly selected and used as pre treated or baseline analysis. Age and sex matched control C57BL/6J mice (n=10 per age group) received the Ad5 LacZ con trol vector using the same protocols. Production of Ad5 LacZ and Ad5 IL17A vectors The recombinant adenovirus vector s used in this study w ere generously provided by Dr. Jay K. Kolls ( Children's Hospital of Pittsburgh Pittsburgh, PA). These vectors are based on the first generation adenovirus serotype 5 (Ad5 ) and shown to produce their appropriate and functional mouse IL 17A and LacZ products [22 24] To obtain sufficient viral vectors for the present studies, ea ch recombinant vector was amplified in HEK293 cells, purified by two rounds of CsCl gradient centrifugation, then dialyzed against 100 mM Tris HCl (pH 7.4), 10 mM MgCl 2 and 10% (v/v) glycerol, as described elsewhere [25] Retrograde salivary gland cannulation of Ad5 LacZ or Ad5 IL17A vectors Previous studies have demonstrated that retrograde salivary gland cannulation is an effective method to direct local gene expression in the salivary glands [26 28] In brief, prior to cannulation, each mouse was anesthetized with a ketamine:xylazine mixture ( 100 mg/mL, 1

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6 mL/kg body weight; Fort Dodge An imal Health, Fort Dodge, IA ) and xylazine (20 mg/mL, 0.7 mL/kg body weight; Phoenix Scientific, St. Joseph, MO ) ) via intramuscularly. Stretched PE 10 polyethylene tubes were inserted into each of the two openings of the salivary ducts. After securing the cannulas, the mouse received an intramuscular injection of atropine (1 mg/kg), followed 10 minutes later by a slow, steady injection of viral vector. Each salivary gland received 50 "l of vector sol ution containing 10 7 viral particles). The cannulas were removed 5 minutes lat er to ensure successful cannulation Measurement of saliva flow To measure stimulated saliva flow individual non anesthetized mice were weighed and given an i.p. injection of 100 l of PBS containing isoproterenol (0.02 mg/ml) and pilocarpine (0.05 mg/ml). Saliva was collected for 10 min from the oral cavity of individual mice using a micropipette starting 1 min after injection of the secretagogue. The volume of each saliva sa mple was measured. Prior to vector cannulation and again at each time point designated in the text, saliva and sera were collected from each mouse. Samples were stored at 80 o C until analyzed. Determination of cytokines levels: Measurements of IL 6 and IL 17A cytokine levels in sera samples were performed by an independent contractor (Millipore, Billerica, MA ) using Luminex¨ platform Intracellular cytokine staining and flow cytometric analysis S pleens were freshly explanted, gently minced through stai nless steel sieves, suspended in phosphate buffered saline (PBS) and centrifuged (1200rpm for 5 minutes). Erythrocytes were lysed by 7 minute incubation in 0.84% NH4Cl. The resulting leukocyte suspensions were washed two times in PBS, counted and resuspend ed inculture media (RPMI 1640 medium, 10% FBS, 2 mM L glutamine, 0.05 mM # mercaptoethanol) at a density of 2 x 10 6 cells/ml. One million cells were pipetted to individual wells of a 24 well microtiter plate pre coated with anti CD3 (10 g/ml) and anti CD2 8 antibodies (2 g/ml) for T cell activation. Cells were incubated for 5 hrs with Leukocyte Activation Cocktail containing GolgiPlug (2 l/ml). Collected cells were

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7 fixed and permeabilized using Cytofix/CytopermFixation/Permeabilization. Flow cytometric ac quisition for intracellular staining was performed following staining with PE Cy5 conjugated anti mouse CD4, FITC conjugated anti IFN and PE conjugated anti IL 17A A. The cells were counted on a FACSCalibur (BD Franklin Lakes, NJ ) and analyzed by FCS Exp ress (De Novo Software Los Angeles, CA ). Histology Following euthanasia, whole salivary glands containing submandibular, sublingual, and parotid glands were surgically removed from each mouse and placed in 10% phosphate buffered formalin for 24 hrs. Fixe d tissues were embedded in paraffin and sectioned at 5 m thickness. Paraffin embedded sections were de paraffinized by immersing in xylene, followed by dehydrating in ethanol. The tissue sections were prepared and stained with hematoxylin and eosin ( H&E ) dye. Stained sections were observed under a microscope for glandular structure and leukocyte infiltration determination. A double blinded procedure was used to enumerate leukocytic infiltrations (lymphocytic foci) in the histological sections of saliva ry glands. Lymphocytic foci (LF) were defined as aggregates of >50 leukocytes quantified per each histological section. Calculations were based on one histological section per mouse. Immunofluorescent staining for CD3+T cells and B220+B cells Histolog ical sections of salivary gland s were incubated with rat anti mouse B220 (BD Pharmi ngen, San Jose, CA) and goat anti mouse CD3 (Santa Cruz Biotechnology, Santa Cruz, CA), followed by incubation with Texas Red conjugated rabbit anti rat IgG (Biomed a, Foste r City, CA) and FITC conjugated rabbit anti goat IgG (Sigma Aldrich, St. Lo uis, MO). The slides were mounted with DAPI mounting medium (Vector Laboratories, Burlingame, CA) Sections were observed at 200X magnification using a Zeiss Axiovert 200M microsco pe.and images were obtained with AxioVs40 software (Ver. 4.7.1.0, Zeiss) (Carl Zeiss, Thornwood, Enumeration of B T cells and total number of nuclei in the LF were performed using Mayachitra imago software (Mayachitra, Inc, Santa Barbara, CA)

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8 Immunohis tochemical staining for IL17 A in salivary glands Immunohistochemical staining for IL17A were carried out as previously described [8] In brief, p araffin embedded salivary glands were deparaffinized by immersion in xylene, followed by antigen retrieval with 10 m M citrate buffer, pH 6.0 Tissue sections were incuba ted overnight at 4¡C with anti IL 17 A antibody (Santa Cruz Biotechnology Santa Cruz, CA). Isotyp e controls were done with rabbit IgG The slides were incubated with biotinyl ated goat anti rabbit IgG followed by horseradish peroxidase conjugated strepavidin incubation using the Vectastain ABC kit. The staining was developed by using diaminobenzidine substrate (Vector Laboratories, Burlingame, CA ), and counterstaining was perfo rmed with hematoxylin. Sections were observed at 200X magnification using a Zeiss Axiovert 200M microscope. And images were obtained with AxioVs40 software (Ver. 4.7.1.0, Zeiss) (Carl Zeiss, Thornwood). Enumeration of IL17 A positive cells was performed o n the entire histological sections of the whole salivary glands using Mayachitra imago software (Mayachitra, Inc, Santa Barbara, CA) although lymphocytic infiltrations are normally seen only in the submandibular glands. Detection of antinuclear antibo dies (ANA ) in the sera ANA in the sera of mice were detected using HEp 2 ANA kit (INOVA Diagnostics, Inc, San Diego, CA). All procedures were performed per manufacturer's instructions. In brief, HEp 2 fixed substrate slides were overlaid with appropri ate mouse sera diluted 1:40, 1:80 and 1:160. Slides were incubated for 1 hr at room temperature in a humidified chamber. After three washes for five minutes with PBS, the substrate slides were covered with Alexa 488 conjugated goat anti mouse IgG (H/L) ( Invitrogen Inc, Carlsbad, CA) diluted 1:100 for 45 min at room temperature. After three washes, fluorescence was detected by fluorescence microscopy at 200X magnification using a Zeiss Axiovert 200M microscope and all images were obtained with AxioVs40 so ftware with constant exposure of 0.3 seconds (Carl Zeiss, Thornwood, NY).

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9 Negative control s are secondary antibody only and positive control s are standard serum with nuclear speckled pattern provided with the kits D ata presented in the results are from slides using 1:40 dilutions of sera from each experimental group. Statistical analyses Statistical evaluat ions were determined by using Mann Whitney U test generated by the GraphPad InStat software ( GraphPad Software La Jolla, CA) The two tailed p val ue <0.05 w as considered significant.

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10 RESULTS Induction of IL 17A and IL 6 cytokine levels in sera following transduction with Ad5 IL17A vector Adenoviral vectors have been reported to show peak gene expressions around day 5 post infusion which then persist for approximately 2 wks [29] In the current study i mmunohistochemi cal s taining for the presence of Lac Z protein in the infused salivary glands demonstrate d that optimal transduction efficiency was approximately 26 5% at 2 wks post infusion which decreased to 15 3% by 9 wks post infusion The cells within the salivary gla nds positive for LacZ expression were predominantly ductal cells, as expected, and acinar cells (data not shown) indicating the virus was capable of passing through the ducts. To determine if transduction of salivary glands with IL 17A alters the serum cytokine profiles, serum preparations were assessed for temporal changes in pro inflammatory cytokine levels. S era of treate d mice were collected at days 5 and 12 post treatment to determine the efficacy of the IL 17A expressing viral vectors to affect cy tokine secretions. As shown in Figure 1 C57BL/6J mice treated with the Ad5 IL17A vector at 10 7 viral particles per salivary gland exhibited a marked increase in the level s of serum IL 17A compared to baseline levels or with C57BL/6J mice receiving the co ntrol Ad5 LacZ vector at 10 7 viral particles per salivary gland demonstrating the efficacy of this viral vector to produce IL 17A In addition, Ad5 IL17A treated C57BL/6J mice also secr eted elevated amount s of the IL 17A related cytokine IL 6 following c annulation Thus, the vectors gain access into the glands and apparently secrete IL 17A in quantities that elevate systemic levels. Increas e d number s of IL 17A producing CD4+ T cells in the spleens of Ad5 IL17A transduc ed mice

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11 As mentioned previo usly, s alivary glands were cannulated with Ad5 IL17A vector at either 7 wks or 16 wks of age. T he time points chosen are based on extensive studies of the development and onset of disease in our C57BL/6.NOD Aec1Aec2 mouse model of S S [1 3, 30, 31] The two time points selected represent the innate and adaptive immune response phases, respectively, in the disease mode l, thus they were chosen to mimic these changes in the parental C57 BL/6 mouse. Microarray analyses examined the temporal differential gene expression of salivary and lacrimal glands of C57BL/6 mice revealed gradual change in pathophysiological related genes from 16 20 wks of age, concomitantly, leukocyte infiltration in the exocrine glands is often obse rved at these age s [32, 33] Thus, it is important to examine the role of I L17 A in the development of SS at prior and post to any pathophysiological changes. Mice treated with Ad5 IL17A or Ad5 LacZ at either 7 w ks or 16 wks of age were euthanized at 26 and 27 wks of age i.e. 19 wks and 11 wks post treatment, respectively S plenocytes were isolated from individual mice and examined for the number of IFN and IL 17A secreting CD4+T cells. Representative data, presented in Figures 2 B & C revealed that the number of IL 17A secreting CD4+T cells in the spleens of mice receiving the Ad5 IL17A vector at 7 wks of age was approximately 2 fold higher than m ice receiving the control Ad5 LacZ vector, while the number of IFN secreting CD4+T cells was approximately half at time of analysis. Similarly, the number of IL 17A secreting CD4+T cells in the spleens of mice receiving the Ad5 IL17A vector at 16 wks of age was approximately 7 fold higher than mice receiving the control Ad5 LacZ vector, while the number of IFN secreting CD4+T cells was less than 50% at time of analysis ( Figure 2E & F ). Results of a similar analysis with untreated mice performed one wk prior to vector cannulations are presented in Figures 2A & D Th ese data suggest that even though the Ad5 vector is considered local ly restricted the effect i n C57BL/6 J mice appeared systematic More importantly, the systemic effect s of IL17A in Ad5 ap pears to be correlate with the duration of gene expression after vector cannulation as evidenced by the 2 fold increase in the level s of IL 17A secreting cells at 19 wks post treatment in younger mice but

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12 a 7 fold increase at 11 wks post treatment in the o ld er group. However, one cannot rule out the possibility that different efficacies are achieved based on the status of disease development in different ages of mice. Induction of SS immune pathology in C57BL/6 mice following treatment with Ad5 IL17A vect or Lymphocyte i nfiltration of the salivary and/or lacrimal glands is a critical criterion for identification of the autoimmune phase of S S in both human and animal models. Although the number of LF present in the salivary and lacrimal glands does not ofte n correlate directly with disease or its severity S S patients and NOD derived mouse strains exhibiting SS like disease typically have lymphocytic infiltrates in their salivary glands IL 17A appears to play a critical role in the development of LF and ha s recently been found to be present within LF in both SS patients and animal models [8] Salivary glands of C57BL/6J mice following cannulation with Ad5 IL17A vector were examined for the presence of infiltrating leukocytes S alivar y glands retrieved from C57BL/6J mice treated with Ad5 LacZ vector at either 7 or 16 wks of age revealed that 10% (1 of 10) in each group had evidence of glandular infiltrations ( Figure 3A, B, G, H, Table 1 ). This observation is consistent with the numbe r of healthy, untreated C57BL/6J mice expected to have infiltration of the salivary glands [8] In contrast, salivary glands from C57BL/6J mice treated with Ad5 IL17A vector at 7 wks of age showed infiltrations in 91% (10 of 11 ) with the mean LF per histological section numbering 4 + 1.32 while salivary glands from C57BL/6J mice treated with Ad5 IL17A vector at 16 wks of age revealed infiltrations in 75% (6 of 8) with a mean LF number per histological section of 2 + 0.83 ( Table 1 ) Besides the number of LF detected in the salivary glands of the experimental animals, i mmunofluorescent staining to detect B and T cells revealed further differences in the cellular composition of the infiltrations betwe en mice administered Ad5 IL17A at a n early or late stage At time of euthanasia, C57BL/6J mice treated with Ad5 IL17A vector at 7 wks of age generally

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13 exhibited smaller foci containing fewer IL 17 positive cells compared to mice receiving the vector at 16 wks of age ( Figure 3 C F & I L ) Consistent with previous observation, the smaller foci in mice treated at 7 wks of age may have resulted from the longer duration of time after cannulation (19 wks) reflecting the decrease s in IL 17A serum levels and IL 17 A positive cell numbers. Detail ed examination of IL 17A positive cells revealed that a majority of IL 17A cells are present in the LF and ductal cells with smaller percentage of positive cells found in the epithelium and acinar cells. Nevertheless, these data support the concept that f ormation and maintenance of LF are due, in part, to the expression levels of IL17 A in the salivary glands. Changes in ANA profiles following instillation of the Ad5 IL 17A vector With the appearance of B and T lymphocytes within the salivary glands of A d5 IL17A treated C57BL/6 mice, plus the significant changes within their splenic T H 17 and T H 1 cell population s the presence of circul ating autoantibodies, specifically ANA detectable by staining of HEp 2 cells was examined To identify the pr esence of A NA the sera prepared from blood samples collected from each C57BL/6J mouse both pre and post cannulation were tested for reactivity on HEp 2 cells. As presented in Figure 4 A the sera collected from C57BL/6J mice at 6 wks of age or one wk prior to vecto r treatment showed a general weak ly diffused cytoplasmic and nuclear background staining of the individual target cells. However, sera collected 19 wks post treatment from mice treated with Ad5 IL17A vector at 7 wks of age showed no cytoplasmic staining wi th course speckled staining and negative nucleoli while Ad5 LacZ treated mice exhibited diffused cytoplasmic staining, weak but fine speckled nucleoplasmic staining with negative nucleoli ( Figure s 4 B & C ) Similar result s w ere seen in C7BL/6J mice whose salivary glands were transduced with Ad5 IL17A vector at 16 wks of age in which the pattern was pronounced course speckled staining with no cytoplasmic staining and negative nucleoli at 29 wks of age or 11 wks post treatment ( Figure s 4 D F ). Considering t he functions of IL 17A, it is interesting to see a gradual and subtle change in ANA profile from diffused cytoplasmic/nuclear

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14 pattern to a distinct course nuclear speckled pattern suggesting influence of IL 17A on the B cells repertoire. Induction of salivary gland dysfunction in C57BL/6 J mice following cannulation wit h Ad5 IL17A vector To determine if the expression of exogenous IL 17A can induce salivary gland dysfunction, s aliva volumes for each mouse were measured at 1 wk prior to treatment then at 3 5 wk intervals post cannulation. C57BL/6J mice that received control Ad5 LacZ vector at 7 wks of age exhibited stable stimulated saliva volume s at 7 wks post treatment with a statistically non significant increase in saliva volumes at 11 wks post t reatment. Nevertheless, C57BL/6J mice whose salivary glands were cannulated at 7 wks of age with Ad5 IL17A exhibited a significant and relatively rapid decrease in stimulated saliva volumes that was most pronounced at 7 wks post treatment, and this observ ation is seen even if the saliva volumes are converted to saliva flow rates based on weights of the mice. After 7 wks post treatment, these mice showed a slight recovery ( Figure 5A ) Similar results were observed with C57BL/6J mice cannulated at 16 wks of age with Ad5 LacZ and Ad5 IL17A vectors ; however, no saliva volume recovery was observed at time of euthanization (i.e., 11 wks post treatment) ( Figure 5B ) Whether a reversal of this inhibition would occur in these older animals will require further studies. Thus, saliva secretions of mice receiving the Ad5 IL17A vector were significantly decreased 1 2 months post treatment when compared to secretions of mice receiving the Ad5 LacZ vector.

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15 DISCUSSION The T H 17 derived IL 17A cytokine is a poten t inflammatory cytokine that has been implicated in a growing list of autoimmune diseases, e.g., multiple sclerosis, Crohn's disease, rheumatoid arthritis psoriasis, systemic lupus eryth ematosus, and SS as well as autoimmunity in animal models [3] As the T H 17/ IL 17A system is considered to be an important factor in innate immunity that, in turn, regulates development of the adaptive immune response, it is not surprising that environmental microflora trigger IL 17 A response s [34] The c onsequence of T H 17/ IL 17A activation includes, in addition to the production the IL 17A family of cyto kines, the production of IL 21, IL 22, chemokines ( MIP 2, CXCL1 CXCL2, CXCL5 ), a nd matrix metalloproteases ( MMP3 and MMP 13 ) [16] all actively involved in tissue inflammation. Interaction of the IL 17A with its receptors evokes activation of IL 8, resulting in recruitment of neutrophils to the site of injury. However the relationship between such early innate/inflammatory events mediated by the T H 17/ IL 17A system and the role T H 17 cells play in subsequent autoimmunity remains unknown, especially in light of the multiple functions now associated with the T H 17 cell pop ulations. Thus, in the present stu dy, we have attempted to elucidate the importanc e of the cytokine IL 17A per se in the development of SS and whether its function may be dependent on when it is expressed. Results in which SS non susceptible C57BL/6J mice were cannulated with the Ad5 IL17A vector revealed that increased IL 17A expression could induce several pathological features of SS irrespective of whether the mice received the vector at 7 or 16 wks of age two time points corresponding to innate and a daptive immune responses in SS susceptible C57BL/6.NOD Aec1Aec2 mice This was noted by decreases in saliva production compared to control vector, elevated production of spe cific pro inflammatory cytokine s detected in ser a, change s in the weak cytoplasmic /nuclear ANA pattern s to nuclear specked staining on HEp2 cells and increased numbers of LF and IL17A positive cells present in the salivary glands at

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16 time of euthanasia. Interestingly, mice received Ad5 IL17A at 7 wks of age showed a slight recovery of s aliva secretion at 7 wks of treatment in contrast to mice received Ad5 IL17A at 16 wks of age. This observation might be supported by the differential immunological or biological response of mice at different ages and the effect of Ad5 IL17A exerted on th e mice. Previous studies have indicated that genes placed within Ad5 vectors are generally expressed transiently and locally restricted ( i.e., 7 14 days) [29] T he present study demonstrates that a rapid and significant increase in the levels of plasma IL 17A was affected at 12 days post cannulation by the Ad5 IL17A transgene vector. Interestingly, this systemic increase in IL17 cytokine levels correlated with significant increases in splenic IL 17A secreting CD4+T cells that persisted at least 19 wks for mice treated at 7 wks of age and 11 wks for mice treated at 16 wks of age. Thes e observations indicated that the Ad5 vector effect was longer than anticipated. Whether this effect might be due to an indirect secondary effect of the Ad5 IL17 vector is unknown. In addition, the systemic increase in IL17A production by local treatment of Ad5 IL17A presented in this study is consistent with previous studies by Bruce Baum's laboratory [35 38] Adesanya et al. [39] has demonstrated that acinar cells can be punctured by retrograde salivary gland cannulati on at a certain vector dosage. The injured acinar cells which have compromise d mucosal barrier integrity allow for leakage of the vector systemically. Further studies by Kagami et al. [37] and He et al. [40] provide d evidence that ductal cannulation of salivary glands can also have systemic effects due to the secretory nature of the salivary glands wh ich are well endowed with protein synthesis organelles and secretory machinery. Nevertheless, these observations are consistent with the concept that SS develops along specific biological processes in a sequential fashion and interference with this proc ess alters development of disease [1 3] Therefore, this study clearly indicates the pathogenic nature of IL 17A in inducing SS like phenotypes when cannulated in the salivary glands.

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17 Previous data have shown t hat lymphocytic infiltrates in the salivary glands secret ing IL 17A and its related cytokines are more important in local glandular destruction. Staining salivary glands for IL 17A revealed that C57BL/6 J mice receiv ing Ad5 IL17A vector not only expressed significant level s of IL 17A but that IL 17A levels correlated with recruitment of inflammatory cells, specifically B and T cells, to the glands This observation is important in light of the recent study suggest ing IL 17A is a critical factor in the ada ptive immune response by inducing the formation of germinal centers for the production of autoreactive antibodies [24] A utoantibodies represent a major component in the onset of SS thus the change s in the ANA pro files observed with sera of C57BL/6J mice cannulated with the Ad5 IL17A vector indicate that IL 17A affects even the B cell compartment in SS non susceptible mice T he presence of LF and loss of saliva secretion raise s an interesting question about the po ssible role of IL 17A in B cell activation. As BAFF is capable of inducing T H 17 cell differentiation in addition to regulating B cell activation [41] t he possible role of BAFF and IL17A in this phenomenon needs to be better defined in SS pathogenesis

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18 CONCLUSIONS The capability of IL 17A to induce features of SS in SS non susceptible mice demonstrates the major role this cytokine plays in the development, a nd possibly onset, of the autoimmune process. How this on e cytokine affects the various features of autoimmunity, and at what level or time point, will require additional studies. More importantly, the study demonstrates that IL 17A might be a potential therapeutic target for SS.

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19 LIST OF ABBREVATIONS SS: Sjš gren's Syndrome, IL: Interleukin, Ad5: Adenovirus serotype 5, IFN : Interferon EAE: Experimental autoimmune encephalomyelitis, CIA: Collagen induced arthritis, LF: Lymphocytic Focus, ANA: Antinuclear antibodies, MIP 2: Macrophage inflammatory protein 2, CXCL1: Chemokine (C X C motif) ligand, MMP: matrix metall oproteases, BAFF: B cell activating factor.

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20 COMPETING INTERESTS The authors declare no conflicts of interest.

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21 AUTHORS' CONTRIBUTIO NS JAC produced and determined the titers of the Ad5 LacZ and Ad5 IL17A viral vectors. HY and BL pe rformed retrograde ductal cannulations/instillations of the vectors into the salivary glands. CQN designed the study, performed saliva flow, flow cytometry, histology and statistical analyses, and prepared the manuscript. WC carried out the ANA staining. ABP assisted in the manuscript preparation. All authors read and approved the final manuscript.

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22 ACKNOWLEDGEMENTS The authors would like to thank Dr. Jay K. Kolls and Dr. Julie Bindas (Children's Hospital of Pittsburgh) for generousl y providing the Ad5 LacZ and Ad5 IL17A vectors and Dr. Phil Cohen for his critical reading of the manuscript and helpful suggestions. We greatly appreciate the assistance of Dr. Craig Meyers and Dr. Nicholas Muzyczka for the use of the microscope. Publication of this ar ticle was funded in part by the University of Florida Open Access publishing Fund

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23 FUNDING This work was supported by PHS grants K99DE018958 (CQN) from NIDCR, R21AI081952 (ABP) from NIAID and funds from the Sjšgren's Sy ndrome Foundation and Center for O rphan Autoimmune Disorders HY and JAC were supported by an NIH, NIDCR intramural research grant.

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24 REFERENCES 1. Nguyen CQ, Cha SR, Peck AB: Sjšgren's syndrome (SjS) like disease of mice: the importance of B lymphocytes and au toantibodies Frontiers in Bioscience 2007, 12 :1767 1789. 2. Nguyen CQ, Peck AB: Unraveling the pathophysiology of Sjogren syndrome associated dry eye disease Ocul Surf 2009, 7 :11 27. 3. Lee BH, Tudares MA, Nguyen CQ: Sjogren's syndrome: an old tale with a new twist Arch Immunol Ther Exp (Warsz) 2009, 57 :57 66. 4. Brayer JB, Cha S, Nagashima H, Yasunari U, Lindberg A, Diggs S, Martinez J, Goa J, Humphreys Beher MG, Peck AB: IL 4 dependent effector phase in autoimmune exocrinopathy as defined by the NOD.IL 4 gene knockout mouse model of Sjogren's syndrome Scand J Immunol 2001, 54 :133 140. 5. Cha S, Brayer J, Gao J, Brown V, Killedar S, Yasunari U, Peck AB: A dual role for interferon gamma in the pathogenesis of Sjogren's syndrome like autoimmune exocrinopa thy in the nonobese diabetic mouse Scand J Immunol 2004, 60 :552 565. 6. Nguyen KH, Brayer J, Cha S, Diggs S, Yasunari U, Hilal G, Peck AB, Humphreys Beher MG: Evidence for antimuscarinic acetylcholine receptor antibody mediated secretory dysfunction in no d mice Arthritis Rheum 2000, 43 :2297 2306. 7. Nguyen CQ, Gao JH, Kim H, Saban DR, Cornelius JG, Peck AB: IL 4 STAT6 signal transduction dependent induction of the clinical phase of Sjogren's syndrome like disease of the nonobese diabetic mouse J Immunol 2007, 179 :382 390. 8. Nguyen CQ, Hu MH, Li Y, Stewart C, Peck AB: Salivary gland tissue expression of interleukin 23 and interleukin 17 in Sjogren's syndrome: Findings in humans and mice Arthritis Rheum 2008, 58 :734 743.

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25 9. Sakai A, Sugawara Y, Kuroishi T Sasano T, Sugawara S: Identification of IL 18 and Th17 cells in salivary glands of patients with Sjogren's syndrome, and amplification of IL 17 mediated secretion of inflammatory cytokines from salivary gland cells by IL 18 J Immunol 2008, 181 :2898 2906 10. Harrington LE, Hatton RD, Mangan PR, Turner H, Murphy TL, Murphy KM, Weaver CT: Interleukin 17 producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineages Nat Immunol 2005, 6 :1123 1132. 11. Park H, Li Z, Ya ng XO, Chang SH, Nurieva R, Wang YH, Wang Y, Hood L, Zhu Z, Tian Q et al : A distinct lineage of CD4 T cells regulates tissue inflammation by producing interleukin 17 Nat Immunol 2005, 6 :1133 1141. 12. Veldhoen M, Hocking RJ, Atkins CJ, Locksley RM, Stocki nger B: TGFbeta in the context of an inflammatory cytokine milieu supports de novo differentiation of IL 17 producing T cells Immunity 2006, 24 :179 189. 13. Bettelli E, Carrier Y, Gao W, Korn T, Strom TB, Oukka M, Weiner HL, Kuchroo VK: Reciprocal develop mental pathways for the generation of pathogenic effector TH17 and regulatory T cells Nature 2006, 441 :235 238. 14. Mangan PR, Harrington LE, O'Quinn DB, Helms WS, Bullard DC, Elson CO, Hatton RD, Wahl SM, Schoeb TR, Weaver CT: Transforming growth factor beta induces development of the T(H)17 lineage Nature 2006, 441 :231 234. 15. Ivanov, II, McKenzie BS, Zhou L, Tadokoro CE, Lepelley A, Lafaille JJ, Cua DJ, Littman DR: The orphan nuclear receptor RORgammat directs the differentiation program of proinflamm atory IL 17+ T helper cells Cell 2006, 126 :1121 1133. 16. Weaver CT, Hatton RD, Mangan PR, Harrington LE: IL 17 family cytokines and the expanding diversity of effector T cell lineages Annu Rev Immunol 2007, 25 :821 852.

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26 17. Kastelein RA, Hunter CA, Cua D J: Discovery and biology of IL 23 and IL 27: related but functionally distinct regulators of inflammation Annu Rev Immunol 2007, 25 :221 242. 18. Zhou L, Lopes JE, Chong MM, Ivanov, II, Min R, Victora GD, Shen Y, Du J, Rubtsov YP, Rudensky AY et al : TGF be ta induced Foxp3 inhibits T(H)17 cell differentiation by antagonizing RORgammat function Nature 2008, 453 :236 240. 19. Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A et al : A genome wide a ssociation study identifies IL23R as an inflammatory bowel disease gene Science 2006, 314 :1461 1463. 20. Hue S, Ahern P, Buonocore S, Kullberg MC, Cua DJ, McKenzie BS, Powrie F, Maloy KJ: Interleukin 23 drives innate and T cell mediated intestinal inflamm ation J Exp Med 2006, 203 :2473 2483. 21. Cua DJ, Sherlock J, Chen Y, Murphy CA, Joyce B, Seymour B, Lucian L, To W, Kwan S, Churakova T et al : Interleukin 23 rather than interleukin 12 is the critical cytokine for autoimmune inflammation of the brain Nat ure 2003, 421 :744 748. 22. Ye P, Rodriguez FH, Kanaly S, Stocking KL, Schurr J, Schwarzenberger P, Oliver P, Huang W, Zhang P, Zhang J et al : Requirement of interleukin 17 receptor signaling for lung CXC chemokine and granulocyte colony stimulating factor expression, neutrophil recruitment, and host defense J Exp Med 2001, 194 :519 527. 23. Schwarzenberger P, La Russa V, Miller A, Ye P, Huang W, Zieske A, Nelson S, Bagby GJ, Stoltz D, Mynatt RL et al : IL 17 stimulates granulopoiesis in mice: use of an alter nate, novel gene therapy derived method for in vivo evaluation of cytokines J Immunol 1998, 161 :6383 6389. 24. Hsu HC, Yang P, Wang J, Wu Q, Myers R, Chen J, Yi J, Guentert T, Tousson A, Stanus AL et al : Interleukin 17 producing T helper cells and interle ukin 17 orchestrate

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27 autoreactive germinal center development in autoimmune BXD2 mice Nat Immunol 2008, 9 :166 175. 25. Zheng C, Baum BJ: Evaluation of promoters for use in tissue specific gene delivery Methods Mol Biol 2008, 434 :205 219. 26. Kok MR, Yaman o S, Lodde BM, Wang J, Couwenhoven RI, Yakar S, Voutetakis A, Leroith D, Schmidt M, Afione S et al : Local adeno associated virus mediated interleukin 10 gene transfer has disease modifying effects in a murine model of Sjogren's syndrome Hum Gene Ther 2003 14 :1605 1618. 27. Kok MR, Voutetakis A, Yamano S, Wang J, Cotrim A, Katano H, Bossis I, Chiorini JA, Tran SD, Tak PP et al : Immune responses following salivary gland administration of recombinant adeno associated virus serotype 2 vectors J Gene Med 2005 7 :432 441. 28. Lodde BM, Mineshiba F, Wang J, Cotrim AP, Afione S, Tak PP, Baum BJ: Effect of human vasoactive intestinal peptide gene transfer in a murine model of Sjogren's syndrome Ann Rheum Dis 2006, 65 :195 200. 29. Delporte C, Redman RS, Baum BJ: R elationship between the cellular distribution of the alpha(v)beta3/5 integrins and adenoviral infection in salivary glands Lab Invest 1997, 77 :167 173. 30. Cha S, Nagashima H, Brown VB, Peck AB, Humphreys Beher MG: Two NOD Idd associated intervals contrib ute synergistically to the development of autoimmune exocrinopathy (Sjogren's syndrome) on a healthy murine background Arthritis Rheum 2002, 46 :1390 1398. 31. Brayer J, Lowry J, Cha S, Robinson CP, Yamachika S, Peck AB, Humphreys Beher MG: Alleles from ch romosomes 1 and 3 of NOD mice combine to influence Sjogren's syndrome like autoimmune exocrinopathy J Rheumatol 2000, 27 :1896 1904.

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28 32. Nguyen CQ, Sharma A, Lee BH, She JX, McIndoe RA, Peck AB: Differential gene expression in the salivary gland during dev elopment and onset of xerostomia in Sjogren's syndrome like disease of the C57BL/6.NOD Aec1Aec2 mouse Arthritis Res Ther 2009, 11 :R56. 33. Nguyen CQ, Sharma A, She JX, McIndoe RA, Peck AB: Differential gene expressions in the lacrimal gland during develo pment and onset of keratoconjunctivitis sicca in Sjogren's syndrome (SJS) like disease of the C57BL/6.NOD Aec1Aec2 mouse Exp Eye Res 2009, 88 :398 409. 34. Bettelli E, Korn T, Oukka M, Kuchroo VK: Induction and effector functions of T(H)17 cells Nature 20 08, 453 :1051 1057. 35. Zheng C, Voutetakis A, Kok MR, Goldsmith CM, Smith GB, Elmore S, Nyska A, Vallant M, Irwin RD, Baum BJ: Toxicity and biodistribution of a first generation recombinant adenoviral vector, in the presence of hydroxychloroquine, followin g retroductal delivery to a single rat submandibular gland Oral Dis 2006, 12 :137 144. 36. O'Connell BC, Zheng C, Jacobson Kram D, Baum BJ: Distribution and toxicity resulting from adenoviral vector administration to a single salivary gland in adult rats J Oral Pathol Med 2003, 32 :414 421. 37. Kagami H, O'Connell BC, Baum BJ: Evidence for the systemic delivery of a transgene product from salivary glands Hum Gene Ther 1996, 7 :2177 2184. 38. Wang J, Voutetakis A, Mineshiba F, Illei GG, Dang H, Yeh CK, Baum BJ: Effect of serotype 5 adenoviral and serotype 2 adeno associated viral vector mediated gene transfer to salivary glands on the composition of saliva Hum Gene Ther 2006, 17 :455 463. 39. Adesanya MR, Redman RS, Baum BJ, O'Connell BC: Immediate inflammat ory responses to adenovirus mediated gene transfer in rat salivary glands Hum Gene Ther 1996, 7 :1085 1093.

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29 40. He X, Goldsmith CM, Marmary Y, Wellner RB, Parlow AF, Nieman LK, Baum BJ: Systemic action of human growth hormone following adenovirus mediated gene transfer to rat submandibular glands Gene Ther 1998, 5 :537 541. 41. Doreau A, Belot A, Bastid J, Riche B, Trescol Biemont MC, Ranchin B, Fabien N, Cochat P, Pouteil Noble C, Trolliet P et al : Interleukin 17 acts in synergy with B cell activating fact or to influence B cell biology and the pathophysiology of systemic lupus erythematosus Nat Immunol 2009, 10 :778 785.

PAGE 30

30 FIGURE LEGENDS: Figure 1. Rapid changes in IL 17A and IL 6 serum cytokine concentrations in C57BL/6J mice following vector cannulat ions. Sera were prepared from blood collected from individual 5 wk old mice (n=4) randomly chosen 1 wk prior to vector treatment (day 0 on the graph). Mice were allowed to acclimate for 7 days, followed by vector instillation of each salivary gland with 50 l of vector solution containing 10 7 viral particles of either Ad5 LacZ or Ad5 IL17A vector. Sera were again prepared from blood collected from individual mice (n=11) at day 5 and day 12 post treatment. Concentrations of cytokines were determined usin g the Luminex platform. To ensure sufficient quantities for testing, the sera of three individual mice of each experimental group were pooled. ND: not detected indicates levels below threshold detection. Figure 2 Intracellular staining for IL 17A an d IFN secreting CD4 + T cells in spleens of Ad5 I L17A treated mice Splenic leukocytes prepared from C57BL/6J mice (n=4) at 6 wks of age (one wk prior to vector treatment) and 26 wks old (19 wks post vector treatment), considered early treatment ( A C ), or splenic leukocytes prepared from C57BL/6J mice (n=4) at 15 wks of age (one wk prior to vector treatment) and 27 wks old (11 wks post vector treatment), considered late treatment ( D F ) were examined for the presence of intracellular IL 17A and IFN gated on CD4 + T cells following a 5 hr in vitro activation with anti CD3$ and anti CD28 in Leukocyte Activation Cocktail containing GolgiPlug. Flow cytometric acquisition was performed by staining with PE Cy5 conjugated rat anti CD4, FITC conjugated rat anti IFN! and/or PE conjugated rat anti IL 17A. Data was analyzed by FCS Express. Flow cytometric images shown are from one representative analysis of 2 independent experiments that examined 2 different mice within each exper iment. Data presented as mean + SEM for n=4 per group and statistical analyses were performed comparing the means of the Ad LacZ and Ad IL17A treated groups at

PAGE 31

31 26 wks and 27 wks of early and late treatment, respectively. (*) indicates p<0.5 using Mann Wh itney U test. Figure 3 Histological examination of salivary glands Salivary gland histology was examined at 19 wks post vector infusions of mice treated at 7 wks of age (early treatment) or at 11 wks post vector infusions of mice treated at 16 wks of age (late treatment). Panels show representative H&E staining of salivary gland tissue from mice receiving early treatment with Ad5 LacZ (n=10) ( A ), or Ad5 IL17A (n=11) ( B ); fl uorescent staining and enumeration of B and T cells in Ad5 IL17 A treated mice ( C & D ) and immunohistochemical staining and enumeration of IL 17 A positive cells in Ad5 IL17 A treated mice ( E & F ) ; H&E staining of s alivary gland tissue from mice receiving late treatment with Ad5 LacZ ( n=10 ) ( G ), or Ad5 IL17 ( n=8) ( H ); and fluorescent staining and enumeration of B and T cells in Ad5 IL17 A treated mice ( I & J ) and immunohistochemical staining and enumeration of IL 17 A positive cells in Ad5 IL17 A treated mice ( K & L ). Black arrows indicate representative lymphocytic infiltrate. Figure 4 Identification of the antinuclear antibodies in sera of C57BL/6J mice Representative patterns of cellular staining of HEp 2 cells by sera diluted at 1:40 prepared from sera taken from C57BL/6 mice cannulated with Ad5 LacZ or Ad5 IL17A vectors at 7 wks of age with pre treated mice (baseline) at 6 wks of age (n=4) ( A C ), and cannulated at16 wks of age with Ad5 LacZ or Ad5 IL17A and pre treated mice (baseline) at 15 wks of age (n=4) ( D F ) with negative control using secondary antibody only ( G) and positive control with standard nuclear speckled serum ( H) Representative patterns were determined with n=4 for two baselines and n=7 for each time point presented in the figure. Fixed HEp 2 substrate slides were incubated with individual mouse sera diluted 1:40 1:80 and 1:160 followed by development with FITC conjugated goat anti mouse IgG. Fluorescent patterns were detected by fluorescence microscopy at 400X magnification.

PAGE 32

32 Figure 5. S timulated s aliva flow in treated C57BL/6 J mice One week prior to saliva ry gland cannulations with either Ad5 LacZ or Ad5 IL17A vector, stimulated saliva volume s w ere determined for individual mice within each of the four experimental groups: early treatment with Ad5 LacZ (n=10) or Ad5 IL17A (n=11) at 7 wks of age ( A ) or late treatment with Ad5 Lac Z (n=10) or Ad5 IL17A (n=8) at 16 wks of age ( B ). Saliva was collected every 3 5 wks post treatment until the mice were euthanized. Statistical analysis was used to determine the significance between the Ad5 LacZ and Ad5 IL17A trea ted mice at each time point. (NS: not significant, p=*<0.05, p=**<0.01 p=***<0.001 ) Arrows indicate the initial time point of vector cannulation

PAGE 33

33 Table 1: Quantification of lymphocytic foci (LF) in salivary glands Ad5:LacZ Ad5:IL17A No LF LF Mea n LF No LF LF Mean LF Early 9 a (90%) b 1 (10%) 1 1 (9%) 10 (91%) 4 + 1.32 c Late 9 (90%) 1 (10%) 1 2 (25%) 6 (75%) 2 + 0.83 a number of mice b percentage of mice c mean number of LF + SEM per histological salivary gland section LF; lymphocytic foci, Ad5; Adenovirus serotype 5, IL; interleukin.

PAGE 34

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P26_SP00152 1365
P26_ST00167 1384
P26_SP00153 1518
P26_ST00168 1533 2003, 0.40 58880
P26_SP00154 1642 1825
P26_ST00169 1661 421:744-748.
P26_TL00016 1891 1856
P26_ST00170 22.
P26_SP00155
P26_ST00171 53 Ye
P26_SP00156 504
P26_ST00172 523
P26_SP00157 557 1930
P26_ST00173 203 Rodriguez
P26_SP00158 782 1932
P26_ST00174 800 FH,
P26_SP00159 866
P26_ST00175 887 Kanaly
P26_SP00160
P26_ST00176 1038
P26_SP00161 1075
P26_ST00177 1094 170 Stocking
P26_SP00162 1264
P26_ST00178 1285 KL,
P26_SP00163
P26_ST00179 Schurr
P26_SP00164 1498
P26_ST00180 1511
P26_SP00165 1541
P26_ST00181 1560 358 Schwarzenberger
P26_SP00166 1918
P26_ST00182 1934
P26_SP00167
P26_ST00183 1988 Oliver
P26_SP00168 2107
P26_ST00184 2123
P26_TL00017 1997 1752
P26_ST00185 Huang
P26_SP00169 582 2038
P26_ST00186 599
P26_SP00170 649 2036
P26_ST00187 126 Zhang
P26_SP00171 793
P26_ST00188
P26_SP00172 848
P26_ST00189
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P26_ST00190 1009
P26_SP00174 1027 2029
P26_ST00191 1046
P26_SP00175 1084
P26_ST00192 1097 0.72 008
P26_SP00176 1138
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P26_SP00177 1435
P26_ST00194 1451
P26_SP00178 1493
P26_ST00195 224 interleukin
P26_SP00179 1732
P26_ST00196 1753 45
P26_SP00180 1798
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P26_SP00181
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P26_ST00199
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P26_SP00183 617 2143
P26_ST00201 CXC
P26_SP00184 728
P26_ST00202 745 235 chemokine
P26_SP00185 980
P26_ST00203 996
P26_SP00186 1072
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P26_SP00188 1765
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P26_TL00019 2207 1536
P26_ST00208 neutrophil
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P26_ST00210 965
P26_SP00192 1042 2239
P26_ST00211 1062 host
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P26_ST00212 1170 179 defense.
P26_SP00194 1349
P26_ST00213 1369 0.14 8
P26_SP00195 1392
P26_ST00214 1404 0.16 888
P26_SP00196 1481
P26_ST00215 1496 Wed 0.25 8848
P26_SP00197 1585
P26_ST00216 1597 2001,
P26_SP00198 1706
P26_ST00217 1728 261 194:519-527.
P26_TL00020 2313 1902
P26_ST00218 23.
P26_SP00199 2345
P26_ST00219
P26_SP00200 810 2354
P26_ST00220 826
P26_SP00201 860 2352
P26_ST00221 882 44 La
P26_SP00202 926
P26_ST00222 946 Russa
P26_SP00203 1069
P26_ST00223 1085 V,
P26_SP00204 1123
P26_ST00224 1143 Miller
P26_SP00205 1251
P26_ST00225 1263 A,
P26_SP00206 1301
P26_ST00226 1320
P26_SP00207 1372
P26_ST00227
P26_SP00208 1426
P26_ST00228 1448
P26_SP00209
P26_ST00229 1592
P26_SP00210
P26_ST00230 132 Zieske
P26_SP00211 1793
P26_ST00231
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P26_ST00232 1868 Nelson
P26_SP00213 2003
P26_ST00233
P26_SP00214
P26_ST00234 124 Bagby
P26_TL00021 2418 1683
P26_ST00235 GJ,
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P26_ST00236 536 Stoltz
P26_SP00216 647 2450
P26_ST00237 D,
P26_SP00217 703
P26_ST00238 Mynatt
P26_SP00218 857 2459
P26_ST00239 874 RL
P26_SP00219 927
P26_ST00240 944
P26_SP00220
P26_ST00241 995
P26_SP00221
P26_ST00242 IL-17
P26_SP00222 1158
P26_ST00243 1174 stimulates
P26_SP00223 1398
P26_ST00244 1415 321 granulopoiesis
P26_SP00224 1736
P26_ST00245 1755 in
P26_SP00225
P26_ST00246 mice:
P26_SP00226 1919
P26_ST00247 2426 use
P26_SP00227 2014
P26_ST00248 2031
P26_SP00228 2073
P26_ST00249 2086
P26_TL00022 2524 1792
P26_ST00250 199 alternate,
P26_SP00229 650 2563
P26_ST00251 novel
P26_SP00230 783 2556
P26_ST00252 801 2532 102 gene
P26_SP00231 903 2565
P26_ST00253 919 340 therapy-derived
P26_SP00232
P26_ST00254 method
P26_SP00233
P26_ST00255 1454
P26_SP00234 1516
P26_ST00256 1530
P26_SP00235 1564
P26_ST00257 1582 88 vivo
P26_SP00236 1670
P26_ST00258 1686 222 evaluation
P26_SP00237 1908
P26_ST00259 1927
P26_SP00238
P26_ST00260 1983 cytokines.
P26_SP00239 2200
P26_ST00261 2220
P26_TL00023 2629 629
P26_ST00262 296 lmmunon998, 0.69 00000288870
P26_SP00240 749 2668
P26_ST00263 770 312 161:6383-6389.
P26_TL00024 2734
P26_ST00264 24.
P26_SP00241 2766
P26_ST00265 Hsu 001
P26_SP00242 528
P26_ST00266 548 HC,
P26_SP00243 618 2773
P26_ST00267 637 Yang
P26_SP00244 739 2775
P26_ST00268 760
P26_SP00245
P26_ST00269 115 Wang 1000
P26_SP00246 928
P26_ST00270 945
P26_SP00247 975
P26_ST00271 993 Wu 11
P26_SP00248 1058
P26_ST00272 1076 Q,
P26_SP00249 1118
P26_ST00273 Myers
P26_SP00250 1258
P26_ST00274 1277
P26_SP00251 1314
P26_ST00275 1333
P26_SP00252
P26_ST00276
P26_SP00253 1484
P26_ST00277 1503 Yi
P26_SP00254 1539
P26_ST00278 1556
P26_SP00255 1586
P26_ST00279 1606 Guentert 0.95 01000002
P26_SP00256 1781
P26_ST00280 T,
P26_SP00257 1831
P26_ST00281 171 Tousson 0010000
P26_SP00258 2020
P26_ST00282 2037
P26_SP00259 2075
P26_ST00283 2095 Stanus 000010
P26_TL00025 2840 1684
P26_ST00284 55 AL 0.66
P26_SP00260 505 2872
P26_ST00285
P26_SP00261 559
P26_ST00286 572
P26_SP00262 613
P26_ST00287 634 225 Interleukin
P26_SP00263 859
P26_ST00288 17-producing
P26_SP00264 1162 2881
P26_ST00289 1180
P26_SP00265 1206
P26_ST00290 1222 136 helper
P26_SP00266 1358
P26_ST00291 1371 98 cells
P26_SP00267
P26_ST00292 1485
P26_SP00268 1562
P26_ST00293
P26_SP00269 1806
P26_ST00294
P26_SP00270 1871
P26_ST00295 1889 245 orchestrate
P26_TB00002 1248 3047
P26_TL00026 1254 3053
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P9_SP00009 1669
P9_ST00010 1686 61
P9_SP00010 1747
P9_ST00011 1765 172 standard
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P9_SP00012 2078 16
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P9_ST00015 465 176 speckled
P9_SP00014 641 456
P9_ST00016 660 416 136 40 pattern
P9_SP00015 796
P9_ST00017 815 provided
P9_SP00016 984
P9_ST00018 1001
P9_SP00017 1079
P9_ST00019 1096 60 the
P9_SP00018 1156
P9_ST00020 1174 74 kits.
P9_SP00019 1248 34
P9_ST00021 1282 91 Data
P9_SP00020 1373
P9_ST00022 1391 197 presented
P9_SP00021 1588
P9_ST00023 1607 30 in 00
P9_SP00022 1637
P9_ST00024 1654
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P9_ST00026 1879 423
P9_SP00025 1941
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P9_ST00028 2062 114 slides 000000
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P9_ST00030 427 82 1:40
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P9_ST00034 859 87
P9_SP00032 946
P9_ST00035 964 94 each
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P9_ST00036 1076 258 experimental 000000000000
P9_SP00034 1334
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P9_ST00040
P9_SP00036 493 869
P9_ST00041 511 228 evaluations
P9_SP00037 739 15
P9_ST00042 754 845 96 were
P9_SP00038 850
P9_ST00043 868 223 determined 0000000000
P9_SP00039 1091 20
P9_ST00044 1111 43 by
P9_SP00040 1154 878
P9_ST00045
P9_SP00041 1275
P9_ST00046 1294 291 Mann-Whitney
P9_SP00042 1585
P9_ST00047 1603 25 U
P9_SP00043 1628
P9_ST00048 1646 838 72 31 test
P9_SP00044 1718
P9_ST00049 1734 201 generated
P9_SP00045 1935
P9_ST00050 1954
P9_SP00046 1997
P9_ST00051 2013
P9_TL00006 942 1939
P9_ST00052 203 GraphPad
P9_SP00047 505 983
P9_ST00053 115 InStat
P9_SP00048 974
P9_ST00054 656 software
P9_SP00049 825
P9_ST00055 218 (GraphPad
P9_SP00050 1061
P9_ST00056 188 39 Software,
P9_SP00051 1267 981
P9_ST00057 1287 45 La
P9_SP00052 1332
P9_ST00058 1348 101 Jolla,
P9_SP00053 1449
P9_ST00059 1469 84 CA). 0.84 0005
P9_SP00054 1553
P9_ST00060 1572 76 The
P9_SP00055 1648
P9_ST00061 1664 192 two-tailed
P9_SP00056 1856
P9_ST00062 1875 950 p
P9_SP00057 1895
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P9_SP00058 2017
P9_ST00064 2035 111 <0.05
P9_SP00059 2146
P9_ST00065 2161 was
P9_TL00007 1048
P9_ST00066 219 considered
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P6_SP00003 690 22
P6_ST00004 712 77 32 Fort
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P6_ST00005 806 129 Dodge 00000
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P6_SP00010 1571
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P6_SP00011 1660 16
P6_ST00012 1676 163 xylazine 00000000
P6_SP00012 1839
P6_ST00013 61 (20
P6_SP00013 1918
P6_ST00014 1936 145 mgmL, 0.93 004000
P6_SP00014 2081
P6_ST00015 2101 59 0.7
P6_TL00002 415 1915
P6_ST00016
P6_SP00015 456
P6_ST00017
P6_SP00016
P6_ST00018
P6_SP00017
P6_ST00019 161 Phoenix
P6_SP00018 873 447
P6_ST00020 888 189 Scientific, 00000000000
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P6_ST00033 1071 each
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P6_ST00034 1184 37 of 00
P6_SP00032 1221 12
P6_ST00035 1233 the
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P6_ST00036 1310 522 31 two
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P6_SP00036 1632
P6_ST00039 1644 60
P6_SP00037 1704
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P6_ST00042 2035 After
P6_TL00004 302 626 1846
P6_ST00043 168 securing
P6_SP00040 470 667
P6_ST00044 487
P6_SP00041 547 658
P6_ST00045 564 cannulas,
P6_SP00042 754 665
P6_ST00046 772
P6_SP00043 833
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P6_ST00049 1186 46 an
P6_SP00046 1232
P6_ST00050 1251 273 intramuscular 0000000000000
P6_SP00047 1524
P6_ST00051 1539 injection
P6_SP00048 1700
P6_ST00052 1719
P6_SP00049 1756 14
P6_ST00053 1770 atropine
P6_SP00050 1931
P6_ST00054 1949 29 (1
P6_SP00051 1978
P6_ST00055 2002 146 mgkg), 0.94 0040000
P6_TL00005 301 732 1769
P6_ST00056 164 followed
P6_SP00052 465 764
P6_ST00057 486 44 10
P6_SP00053 530
P6_ST00058 548 minutes
P6_SP00054 703
P6_ST00059 721 87 later
P6_SP00055 808
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P6_SP00056 866 773
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P6_ST00062 921 slow,
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P6_ST00064 1187 162
P6_SP00060 1349
P6_ST00065 1367
P6_SP00061 1405
P6_ST00066 1417 80 viral
P6_SP00062 1497
P6_ST00067 1514 733 vector.
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P6_ST00068 1680 Each
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P6_ST00069 1795 152
P6_SP00065 1947
P6_ST00070 1964 106 gland
P6_TL00006 827 1892 51
P6_ST00071 837
P6_SP00066 869
P6_ST00072 488 50
P6_SP00067 534
P6_ST00073 |jl 0.69 260
P6_SP00068 583 878
P6_ST00074 601
P6_SP00069 639
P6_ST00075 651 838 125 vector
P6_SP00070 776
P6_ST00076 790 solution
P6_SP00071 942
P6_ST00077 960 204 containing 0000000000
P6_SP00072 1164
P6_ST00078 1185 42 10'^ 0.59 00610
P6_SP00073 1246
P6_ST00079 1261
P6_SP00074
P6_ST00080 1360 particles). 00010000000
P6_SP00075 1550
P6_ST00081 1582 75 The
P6_SP00076 1657
P6_ST00082 1674 180 cannulas
P6_SP00077 1854
P6_ST00083 1869 845 96
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P6_SP00079 2156
P6_ST00085 2174 5
P6_TL00007 945
P6_ST00086 156
P6_SP00080 459 974
P6_ST00087 476
P6_SP00081 563 13
P6_ST00088 576 943 35 to
P6_SP00082 611
P6_ST00089 628 ensure
P6_SP00083
P6_ST00090 781 209 successful
P6_SP00084 990
P6_ST00091 1008 240 cannulation.
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P6_ST00092 296 Measurement 0.84 05000150500
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P6_ST00093
P6_SP00086 656 9
P6_ST00094 saliva
P6_SP00087
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P6_ST00096 To
P6_SP00088
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P6_ST00099 113
P6_SP00091 894
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P6_ST00104 1689
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P6_ST00105 1801 weighed
P6_SP00097 1968 1194
P6_ST00106 1987
P6_SP00098 2058
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P6_ST00110 377
P6_SP00101 539
P6_ST00111 557
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P6_ST00112 69 100
P6_SP00103
P6_ST00113 698
P6_SP00104 728
P6_ST00114 746
P6_SP00105 784
P6_ST00115 799 85 PBS
P6_SP00106 884
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P6_SP00107 1105
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P6_SP00108 1383
P6_ST00118 1402 (0.02
P6_SP00109 1500
P6_ST00119 134 mgml)
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P6_ST00120 1671
P6_SP00111 1742
P6_ST00121 1757 216 pilocarpine
P6_SP00112 1973
P6_ST00122 1991 99 (0.05
P6_TL00011 1364 1709
P6_ST00123 mgml).
P6_SP00113 448
P6_ST00124 468 Saliva
P6_SP00114 588 1396
P6_ST00125 603 1372 was
P6_SP00115 683
P6_ST00126 699 176 collected
P6_SP00116 875
P6_ST00127 892 for
P6_SP00117
P6_ST00128 958
P6_SP00118
P6_ST00129 min
P6_SP00119
P6_ST00130 1104 from
P6_SP00120 1191
P6_ST00131 1208
P6_SP00121 1268
P6_ST00132 1286 oral
P6_SP00122 1357
P6_ST00133 1375 cavity
P6_SP00123 1488
P6_ST00134 1505
P6_SP00124 1542
P6_ST00135 1557
P6_SP00125
P6_ST00136 1761
P6_SP00126 1852
P6_ST00137 1870 103 using
P6_SP00127
P6_ST00138
P6_TL00012 1469 1944
P6_ST00139 244 micropipette
P6_SP00128
P6_ST00140 560 starting 00001000
P6_SP00129 705
P6_ST00141 726 1
P6_SP00130 738 1501
P6_ST00142 762 67
P6_SP00131 829
P6_ST00143 848 90 after
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P6_ST00144 953
P6_SP00133 1115
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P6_SP00134 1171
P6_ST00146 1183
P6_SP00135
P6_ST00147 1260 1470 284 40 secretagogue.
P6_SP00136 1544
P6_ST00148 1563
P6_SP00137 1638
P6_ST00149 1654 volume
P6_SP00138 1799
P6_ST00150 1811
P6_SP00139 1849
P6_ST00151 1862
P6_SP00140 1956
P6_ST00152 1974
P6_SP00141 2087
P6_ST00153 2104 143 sample
P6_TL00013 300 1575 1916
P6_ST00154 1583
P6_SP00142 380 1607
P6_ST00155 397 measured.
P6_SP00143 606
P6_ST00156 640 Prior
P6_SP00144 734
P6_ST00157 747 1576
P6_SP00145
P6_ST00158 798 124
P6_SP00146 922
P6_ST00159 936 229 cannulation
P6_SP00147
P6_ST00160
P6_SP00148 1254
P6_ST00161 1273 again
P6_SP00149 1379 1616
P6_ST00162 1397 36 at
P6_SP00150 1433
P6_ST00163 1448
P6_SP00151
P6_ST00164 1559 200 time-point
P6_SP00152 1759
P6_ST00165 1775 218 designated
P6_SP00153 1993
P6_ST00166 2013 in
P6_SP00154 2042
P6_ST00167 2059
P6_SP00155 2119
P6_ST00168 2135 81 text,
P6_TL00014 1928
P6_ST00169
P6_SP00156 1712
P6_ST00170 432
P6_SP00157 503
P6_ST00171 1688 sera
P6_SP00158
P6_ST00172 621
P6_SP00159 718
P6_ST00173 735
P6_SP00160 911
P6_ST00174 928
P6_SP00161 1015
P6_ST00175 1033
P6_SP00162 1127
P6_ST00176 mouse.
P6_SP00163 1289
P6_ST00177 1321 175 Samples
P6_SP00164 1496 1721
P6_ST00178
P6_SP00165
P6_ST00179 1624 122 stored
P6_SP00166 1746
P6_ST00180 1764 1681
P6_SP00167 1800
P6_ST00181 1814 -80C
P6_SP00168 1927
P6_ST00182 1945 until
P6_SP00169 2022
P6_ST00183 2040 analyzed.
P6_TL00015 739
P6_ST00184 305 Determination 0505100000000
P6_SP00170 607 1818
P6_ST00185 624
P6_SP00171 669
P6_ST00186 208 cytokines 000000050
P6_SP00172 1827
P6_ST00187 903 138 levels: 0.85 0505000
P6_TL00016 1891 1779
P6_ST00188 298 Measurements
P6_SP00173 1923
P6_ST00189 618
P6_SP00174 655
P6_ST00190 671 72 IL-6
P6_SP00175 743
P6_ST00191 761
P6_SP00176 832
P6_ST00192 852 IL-17A
P6_SP00177 981
P6_ST00193 cytokine
P6_SP00178 1932
P6_ST00194 1179 levels
P6_SP00179 1292
P6_ST00195 1309
P6_SP00180 1339
P6_ST00196 1899
P6_SP00181 1442
P6_ST00197 1459 samples
P6_SP00182 1626
P6_ST00198 1640
P6_SP00183 1737
P6_ST00199 1755 performed
P6_SP00184 1958
P6_ST00200 1977
P6_SP00185 2020
P6_ST00201 2037
P6_TL00017 1997
P6_ST00202 249 independent
P6_SP00186 552 2038
P6_ST00203 567 1998 contractor
P6_SP00187 770 2029
P6_ST00204 785 191 (Millipore,
P6_SP00188 976
P6_ST00205 997 Billerica,
P6_SP00189 2036
P6_ST00206 1182 78 MA)
P6_SP00190
P6_ST00207 1279
P6_SP00191 1382
P6_ST00208 202 Luminex
P6_SP00192 1604
P6_ST00209 1621 170 platform.
P6_TL00018 2102 1282
P6_ST00210 264 Intracellular 0001005000001
P6_SP00193 565 2134
P6_ST00211 00000005
P6_SP00194 758 2143
P6_ST00212 staining
P6_SP00195 947
P6_ST00213 962
P6_SP00196 1043
P6_ST00214 1056 92
P6_SP00197 1148
P6_ST00215 cytometric 0000050100
P6_SP00198 1390
P6_ST00216 178 analysis
P6_TL00019 2207
P6_ST00217 Spleens
P6_SP00199 464 2248
P6_ST00218 478 2215
P6_SP00200 575 2239
P6_ST00219 591 133 freshly
P6_SP00201 724
P6_ST00220 205 explanted,
P6_SP00202
P6_ST00221 964 119 gently
P6_SP00203 1083
P6_ST00222 1100 142 minced
P6_SP00204 1242
P6_ST00223 through
P6_SP00205 1410
P6_ST00224 1428 stainless
P6_SP00206 1603
P6_ST00225 1619 steel
P6_SP00207 1711
P6_ST00226 1729 sieves,
P6_SP00208 1865 2246
P6_ST00227 1884 219 suspended
P6_SP00209 2103
P6_ST00228 2122
P6_TL00020 2313 1880
P6_ST00229 phosphate
P6_SP00210 512 2354
P6_ST00230 buffered
P6_SP00211 691 2345
P6_ST00231 710 saline
P6_SP00212 825
P6_ST00232 843 116 (PBS)
P6_SP00213 959
P6_ST00233 977
P6_SP00214
P6_ST00234 1066 222 centrifuged
P6_SP00215 1288
P6_ST00235 1307 (1200rpm
P6_SP00216
P6_ST00236
P6_SP00217 1567
P6_ST00237 1581
P6_SP00218 1602
P6_ST00238 1620 181 minutes).
P6_SP00219
P6_ST00239 1822 Erythrocytes
P6_SP00220 2071
P6_ST00240 2086 2321
P6_TL00021 2418 1788
P6_ST00241 101 lysed
P6_SP00221 404 2459
P6_ST00242 423
P6_SP00222 466
P6_ST00243 483 7
P6_SP00223 504 2450
P6_ST00244 minute
P6_SP00224 654
P6_ST00245 672 incubation
P6_SP00225
P6_ST00246
P6_SP00226 923
P6_ST00247 0.84%
P6_SP00227
P6_ST00248 1086 NH4CI.
P6_SP00228 1225
P6_ST00249 1244
P6_SP00229 1319
P6_ST00250 1337 resulting
P6_SP00230 1504
P6_ST00251 1523 188 leukocyte
P6_SP00231
P6_ST00252 251 suspensions
P6_SP00232 1980
P6_ST00253 1994 2426
P6_TL00022 2524
P6_ST00254 washed
P6_SP00233 455 2556
P6_ST00255 472 2525
P6_SP00234 540
P6_ST00256 556 times
P6_SP00235 662
P6_ST00257
P6_SP00236 709
P6_ST00258 729 PBS,
P6_SP00237 2563
P6_ST00259 844 158 counted
P6_SP00238 1002
P6_ST00260 1020
P6_SP00239 1091
P6_ST00261 1111 258 resuspended
P6_SP00240 1369 2565
P6_ST00262 1388 inculture
P6_SP00241 1556
P6_ST00263 1574 media
P6_SP00242 1694
P6_ST00264 (RPMI
P6_SP00243 1834 23
P6_ST00265
P6_SP00244 1951
P6_ST00266 1969 medium,
P6_SP00245 2137
P6_ST00267 2160 83 10%
P6_TL00023 2619 1820
P6_ST00268 2629 FBS,
P6_SP00246 2668
P6_ST00269 416 2
P6_SP00247 437 2661
P6_ST00270 mM
P6_SP00248 525
P6_ST00271 546 243 L-glutamine,
P6_SP00249 2670
P6_ST00272 809 0.05
P6_SP00250
P6_ST00273 912
P6_SP00251
P6_ST00274 392 |3-mercaptoethanol) 5700000000000000000
P6_SP00252 1393
P6_ST00275 1411 2630
P6_SP00253 1447
P6_ST00276 1462 2637
P6_SP00254 1483
P6_ST00277 density
P6_SP00255 1642
P6_ST00278 1658
P6_SP00256 1696
P6_ST00279 1708
P6_SP00257
P6_ST00280 1745 2638 x
P6_SP00258 1767
P6_ST00281 10^ 0.67 0010
P6_SP00259 1847
P6_ST00282 1863 159 cellsml. 000005000
P6_SP00260
P6_ST00283 2041 One
P6_TL00024 2734 1875
P6_ST00284 123 million
P6_SP00261 426 2766
P6_ST00285 445 cells
P6_SP00262 532
P6_ST00286 2742
P6_SP00263 644
P6_ST00287 pipetted
P6_SP00264 819 2775
P6_ST00288 836 2735
P6_SP00265 871
P6_ST00289 889
P6_SP00266 1074
P6_ST00290 1090 wells
P6_SP00267 1190
P6_ST00291 1206
P6_SP00268
P6_ST00292 1257
P6_SP00269 1278
P6_ST00293 1295 141 24-well
P6_SP00270 1436
P6_ST00294 186 microtiter
P6_SP00271 1641
P6_ST00295 1656 plate
P6_SP00272 1750
P6_ST00296 1768 212 pre-coated
P6_SP00273
P6_ST00297 with
P6_SP00274 2075
P6_ST00298 2093 anti-
P6_TL00025 2840
P6_ST00299 CD3 0.97
P6_SP00275 389 2872
P6_ST00300 407 (10
P6_SP00276 2881
P6_ST00301 |jgml) 0.80 2604000
P6_SP00277 608
P6_ST00302
P6_SP00278 697
P6_ST00303 716 201 anti-CD28
P6_SP00279 917
P6_ST00304 antibodies
P6_SP00280 1140
P6_ST00305 1157 (2
P6_SP00281
P6_ST00306 1211
P6_SP00282 1333
P6_ST00307 1350 forT
P6_SP00283
P6_ST00308 1458 63 cell
P6_SP00284 1521
P6_ST00309 activation.
P6_SP00285 1739
P6_ST00310 Cells
P6_SP00286 1856
P6_ST00311 1871 2848
P6_SP00287
P6_ST00312 1986 192 incubated
P6_SP00288 2178
P6_ST00313 2196
P6_TL00026 2945
P6_ST00314
P6_SP00289 323 2977
P6_ST00315 341 hrs
P6_SP00290 400
P6_ST00316
P6_SP00291 493
P6_ST00317 513 Leukocyte
P6_SP00292 715 2986
P6_ST00318 730 196 Activation
P6_SP00293 926
P6_ST00319 944 Cocktail
P6_SP00294 1102
P6_ST00320 1120
P6_SP00295 1323
P6_ST00321 194 GolgiPlug
P6_SP00296 1535
P6_ST00322 1554
P6_SP00297 1588
P6_ST00323 |jlml). 0.83 26040000
P6_SP00298 1725
P6_ST00324 Collected
P6_SP00299 1930
P6_ST00325
P6_SP00300
P6_ST00326 2051 2953
P6_TL00027 3053
P6_ST00327


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processingSoftware
softwareCreator Kirtas Technologies, Inc.
softwareName BookScan Editor
softwareVersion 3.6
ocrProcessingStep
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TopMargin P27_TM00001 HPOS 0 VPOS 304
LeftMargin P27_LM00001 295 2785
RightMargin P27_RM00001 2254 296
BottomMargin P27_BM00001 3089 211
PrintSpace P27_PS00001 1959
TextBlock P27_TB00001 2583
TextLine P27_TL00001 451 310 1797 41
String P27_ST00001 267 32 CONTENT autoreactive WC 1.00 CC 000000000000
SP P27_SP00001 718 342 17
P27_ST00002 735 185 germinal 00000000
P27_SP00002 920 351 19
P27_ST00003 939 136 center 000000
P27_SP00003 1075 14
P27_ST00004 1089 279 development 00000000000
P27_SP00004 1368
P27_ST00005 1385 34 in 00
P27_SP00005 1419 18
P27_ST00006 1437 269 autoimmune 0000000000
P27_SP00006 1706
P27_ST00007 1724 117 BXD2 0000
P27_SP00007 1841
P27_ST00008 1859 109 mice. 00000
P27_SP00008 1968 20
P27_ST00009 1988 72 Nat 000
P27_SP00009 2060 13
P27_ST00010 2073 175 Immunol 0.93 0000040
P27_TL00002 415 341 39
P27_ST00011 2008,9:166-175. 000000000000000
P27_TL00003 301 521 1756
P27_ST00012 58 25.
P27_SP00010 359 553 92
P27_ST00013 125 Zheng
P27_SP00011 576 562
P27_ST00014 595 C, 0.96
P27_SP00012 634 560 21
P27_ST00015 655 113 Baum
P27_SP00013 768
P27_ST00016 788 57 BJ:
P27_SP00014 845
P27_ST00017 866 225 Evaluation
P27_SP00015 1091
P27_ST00018 1109 42 of
P27_SP00016 1151 15
P27_ST00019 1166 221 promoters 000000000
P27_SP00017 1387 16
P27_ST00020 1403 62 for
P27_SP00018 1465
P27_ST00021 1480 529 73 24 use
P27_SP00019 1553
P27_ST00022 1571
P27_SP00020 1605
P27_ST00023 1622 316 tissue-specific
P27_SP00021 1938
P27_ST00024 1955 102 33 gene
P27_TL00004 452 626 954
P27_ST00025 179 delivery.
P27_SP00022 631 667
P27_ST00026 651 174 Methods 0.97 0000200
P27_SP00023 825 658
P27_ST00027 840 Mol 020
P27_SP00024 913
P27_ST00028 926 77 Biol 0.95 0020
P27_SP00025 1003 11
P27_ST00029 1014 2008, 0.41 58870
P27_SP00026 1123 665
P27_ST00030 1142 264 434:205-219.
P27_TL00005 732 1823
P27_ST00031 26.
P27_SP00027 764 95
P27_ST00032 454 74 Kok
P27_SP00028 528
P27_ST00033 545 76 MR,
P27_SP00029 621 771
P27_ST00034 640 167 Yamano
P27_SP00030 807
P27_ST00035 824 37 S,
P27_SP00031 861
P27_ST00036 882 121 Lodde
P27_SP00032
P27_ST00037 1022 BM,
P27_SP00033 1095
P27_ST00038 1113 116 Wang 1000
P27_SP00034 1229 773
P27_ST00039 1246 30 J,
P27_SP00035 1276
P27_ST00040 1295 288 Couwenhoven 0.98 00100000000
P27_SP00036 1583
P27_ST00041 1603 50 Rl,
P27_SP00037 1653
P27_ST00042 1671 120 Yakar
P27_SP00038 1791
P27_ST00043 1805 36
P27_SP00039
P27_ST00044 1860 Voutetakis 0010000000
P27_SP00040 2071
P27_ST00045 2085 A,
P27_TL00006 837 1602
P27_ST00046 133 Leroith 0000000
P27_SP00041 587 869
P27_ST00047 607 D,
P27_SP00042 644 876
P27_ST00048 663 163 Schmidt
P27_SP00043 826
P27_ST00049 843 43 M,
P27_SP00044 886
P27_ST00050 903 128 Afione
P27_SP00045 1031
P27_ST00051 1048 26 S
P27_SP00046 1074
P27_ST00052 93 etal: 0.83 00008
P27_SP00047 1184
P27_ST00053 1205 112 Local
P27_SP00048 1317
P27_ST00054 1335 382 adeno-associated 0000000000000000
P27_SP00049 1717
P27_ST00055 1735 321 virus-mediated 00000000000000
P27_TL00007 453 942 1725
P27_ST00056 interleukin
P27_SP00050 678 974
P27_ST00057 699 44 10
P27_SP00051 743
P27_ST00058 760 950 103
P27_SP00052 863 983
P27_ST00059 878 172 transfer
P27_SP00053 1050
P27_ST00060 1064 has
P27_SP00054 1138
P27_ST00061 1155 396 disease-modifying 00000000000000000
P27_SP00055 1551
P27_ST00062 1569 145 effects
P27_SP00056 1714
P27_ST00063 1732
P27_SP00057 1765
P27_ST00064 1783 22 a
P27_SP00058
P27_ST00065 148 murine
P27_SP00059 1971
P27_ST00066 1989 model
P27_SP00060 2117
P27_ST00067 2136
P27_TL00008 1222
P27_ST00068 203 Sjogren's 000000020
P27_SP00061
P27_ST00069 671 226 syndrome.
P27_SP00062 897
P27_ST00070 916 Hum
P27_SP00063 1011 1080
P27_ST00071 1028 106 Gene 0010
P27_SP00064 1134
P27_ST00072 Ther 0.94 0002
P27_SP00065 1248 9
P27_ST00073 1257 2003, 0.30 48885
P27_SP00066 1366 1087
P27_ST00074 287 14:1605-1618. 0000000000000
P27_TL00009 1153 1877
P27_ST00075 27.
P27_SP00067 1185
P27_ST00076
P27_SP00068
P27_ST00077
P27_SP00069 1192
P27_ST00078
P27_SP00070 851
P27_ST00079 865
P27_SP00071 904
P27_ST00080 922 168
P27_SP00072 1090
P27_ST00081 1107
P27_SP00073 1143
P27_ST00082 1162 115
P27_SP00074 1277 1194
P27_ST00083 1294
P27_SP00075 1324
P27_ST00084 1344 130 Cotrim
P27_SP00076 1474
P27_ST00085 1490 38
P27_SP00077 1528
P27_ST00086 1550 138 Katano
P27_SP00078 1688
P27_ST00087 1708 H,
P27_SP00079 1745
P27_ST00088 1766 129 Bossis
P27_SP00080 1895
P27_ST00089 1914 I,
P27_SP00081 1931
P27_ST00090 1950 150 Chiorini
P27_SP00082 2100
P27_ST00091 61 JA,
P27_TL00010 1259
P27_ST00092 90 Tran
P27_SP00083 541 1291
P27_ST00093 559 70 SD, 0.99
P27_SP00084 629 1298
P27_ST00094 647 75 Tak
P27_SP00085 722
P27_ST00095 739 55 PP
P27_SP00086 794
P27_ST00096 811
P27_SP00087
P27_ST00097 924 170 Immune
P27_SP00088 1094
P27_ST00098 1267 224 responses
P27_SP00089 1337 1300
P27_ST00099 1352 197 following
P27_SP00090 1549
P27_ST00100 1567 salivary
P27_SP00091
P27_ST00101 1751 gland
P27_SP00092 1867
P27_ST00102 1885 311 administration
P27_TL00011 1364 1667
P27_ST00103
P27_SP00093 494 1396
P27_ST00104 509 271 recombinant
P27_SP00094 780
P27_ST00105 795
P27_SP00095 1177
P27_ST00106 1195 virus
P27_SP00096 1301
P27_ST00107 188 serotype
P27_SP00097 1505 1405
P27_ST00108 1522 2
P27_SP00098 1543
P27_ST00109 1559 vectors.
P27_SP00099 1729
P27_ST00110 1749 23 J
P27_SP00100 1772
P27_ST00111 1786 107
P27_SP00101 1893
P27_ST00112 1909 89 Med
P27_SP00102 1998 12
P27_ST00113 2010 2005, 0.47 58840
P27_TL00012 1469 212
P27_ST00114 7:432-441.
P27_TL00013 1575 1844
P27_ST00115 28.
P27_SP00103 1607
P27_ST00116
P27_SP00104 575
P27_ST00117 594
P27_SP00105 1614
P27_ST00118 687 204 Mineshiba
P27_SP00106 891
P27_ST00119 910 F,
P27_SP00107
P27_ST00120 960
P27_SP00108 1076 1616
P27_ST00121 1093
P27_SP00109
P27_ST00122
P27_SP00110 1272
P27_ST00123 1288 69 AP,
P27_SP00111 1357
P27_ST00124 1375 127
P27_SP00112 1502
P27_ST00125 1519
P27_SP00113 1556
P27_ST00126 1574
P27_SP00114 1649
P27_ST00127 1666 66 PP,
P27_SP00115
P27_ST00128 1753
P27_SP00116 1865
P27_ST00129
P27_SP00117 1943
P27_ST00130 1964 123 Effect
P27_SP00118 2087
P27_ST00131 2103
P27_TL00014 1680
P27_ST00132 143 human
P27_SP00119 596 1712
P27_ST00133 614 231 vasoactive
P27_SP00120
P27_ST00134 195 intestinal
P27_SP00121 1058
P27_ST00135 1077 158 peptide
P27_SP00122 1235 1721
P27_ST00136 1252
P27_SP00123 1354
P27_ST00137 1369
P27_SP00124 1541
P27_ST00138
P27_SP00125 1590
P27_ST00139
P27_SP00126 1629
P27_ST00140 1648 147
P27_SP00127 1795
P27_ST00141 1813
P27_SP00128 1941
P27_ST00142 1960
P27_SP00129 2002
P27_ST00143 2016 202
P27_TL00015 945
P27_ST00144
P27_SP00130 677 1827
P27_ST00145 695 80 Ann 011
P27_SP00131 775 1818
P27_ST00146 791 Rheum
P27_SP00132 936
P27_ST00147 951 65 Dis
P27_SP00133 1016
P27_ST00148 1029 2006, 0.31 48875
P27_SP00134 1825
P27_ST00149 1158 238 65:195-200.
P27_TL00016 1891 1928
P27_ST00150 29.
P27_SP00135 1923
P27_ST00151 Delporte 00000010
P27_SP00136 1932
P27_ST00152 638
P27_SP00137 1930
P27_ST00153 698 166 Redman
P27_SP00138 864
P27_ST00154 884 68 RS,
P27_SP00139 952
P27_ST00155
P27_SP00140 1086
P27_ST00156 1106
P27_SP00141 1164
P27_ST00157 Relationship 200000000000
P27_SP00142 1453
P27_ST00158 1472 176 between
P27_SP00143
P27_ST00159 1665 the
P27_SP00144 1731
P27_ST00160 159 cellular
P27_SP00145 1908
P27_ST00161 1922 246 distribution
P27_SP00146 2168
P27_ST00162 2187
P27_TL00017 450 1997 1798
P27_ST00163
P27_SP00147 516 2029
P27_ST00164 532 331 alpha(v)beta35 000000000000080
P27_SP00148 2038
P27_ST00165 881 integrins
P27_SP00149 1069
P27_ST00166 1085 and
P27_SP00150
P27_ST00167 1179 adenoviral
P27_SP00151 1404
P27_ST00168 1423 184 infection
P27_SP00152
P27_ST00169 1627
P27_SP00153 1661
P27_ST00170 1679
P27_SP00154 1847
P27_ST00171 1863 154 glands.
P27_SP00155 2017
P27_ST00172 2036 Lab
P27_SP00156 2109
P27_ST00173 2127 Invest
P27_TL00018 455 2102 362
P27_ST00174 1997,77:167-173.
P27_TL00019 302 2207 1821
P27_ST00175 30.
P27_SP00157 2239
P27_ST00176 Cha
P27_SP00158
P27_ST00177 549
P27_SP00159 585 2246
P27_ST00178 Nagashima
P27_SP00160 832 2248
P27_ST00179
P27_SP00161 888
P27_ST00180 122 Brown
P27_SP00162 1032
P27_ST00181 VB,
P27_SP00163 1118
P27_ST00182 1139 97 Peck
P27_SP00164 1236
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PAGE 1

1 Pathogenic effect of interleukin 17A in induction of Sjšgren's s yndrome like disease using adenovirus mediated gene transfer Cuong Q. Nguyen 1,2 ,3,4 Hongen Yin 5 Byung Ha Lee 3 Wendy C. Carcamo 3 J ohn A. Chiorini 5 & Ammon B. Peck 3,4,6 1 Eli and Ed ythe L. Broad Institute, 7 Cambridge Center, Cambridge, MA 02142, USA 2 Department of Chemical Engineering, Massachusetts Institute of Technology, 77 Massachusetts Ave, E25 545, Cambridge MA 02139, USA 3 Department of Oral Biology, University of Florida Co llege of Dentistry, 1600 SW Archer Rd, Gainesville, Florida 32610, USA 4 Center for Orphan Autoimmune Disorders, University of Florida College of Dentistry, 1600 SW Archer Rd, Gainesville, Florida 32610 USA 5 National Institute of Dental and Craniofacia l Research, NIH, 10 Center Drive MSC 1190, Bethesda, Maryland 20892 USA 6 Department of Pathology, Immunology & Laboratory Medicine, University of Florida College of Medicine, 1600 SW Archer Rd, Gainesville, Florida 32610 USA Running title: The role o f IL 17A in Sjšgren's Syndrome Address c orrespondence : Cuong Q. Nguyen, PhD Department of Oral Biology PO Box 100424, College of Dentistry University of Florida Gainesville, Florida 32610 USA Telephone: 352 273 8865 FAX: 352 273 882 9 E mail: Nguyen@pathology.ufl.edu

PAGE 2

2 A BSTRACT : Introduction : Sjšgren's syndrome (SS) involves a chronic, progressive inflammation primarily of the salivary and lacrimal glands leading to decreased levels of saliva and tears resulting in dry mouth and dry eye diseases. Seminal findings regarding T H 17 cell population s that secrete predominantly interleukin ( IL ) 17 A ha ve been shown to play an important role in an increasing number of autoimmune diseases, in cluding SS In the present study, we investigated the function of IL 17A on the development and onset of SS Methods : A denovirus serotype 5 (Ad5) vectors expressing either IL 17A or LacZ were infused via retrograde cannulation into the salivary glands of C57BL/6J mice between 6 8 w ee ks of age or between 15 17 w ee ks of age. The mice were characterized for SS phenotypes. Results : D isease profiling indicated that SS non susceptible C57BL/6J mice whose salivary glands received the Ad5 IL17A vector develope d a SS like disease profile, including appearance of lymphocytic foci, increased cytokine levels changes in antinuclear antibody profiles, and temporal loss of saliva flow Conclusions : Induction of SS pathology by IL 17A in SS non susceptible mice s trongly suggest s that IL 17A is an important inflammatory cytokine in salivary gland dysfunction. Thus, localized anti IL17 therapy may be effective in preventing glandular dysfunction

PAGE 3

3 INTRODUCTION Sjšgren's syndrome ( SS ) is a chronic, systemic autoim mune disease characterized most notably by development of dry eyes and dry mouth manifestations, indicative of secretory dysfunction of the lacrimal and salivary glands [1 3] Although the etiology of SS remains un known, intensive studies of an ever expanding number of animal models is beginning to unravel the genetic, molecular and immunological basis for this disease [1] Previous studies have implicated critical roles for both interferon ( IFN ) and interleukin ( IL ) 4 in development and onset of SS like disease in NOD/LtJ and C57BL/6.NOD Aec1Aec2 mice [4, 5] strongly suggesting involvement of T H 1 and T H 2 cell populations, respectively. While IFN regulates cell mediated immunity through activation of macrophages, NK cells and CD8 + T cells, this cytokine appears to predispose these SS susceptible mice by retarding salivary gland organogenesis, especially proliferation of acinar tissue [5] This delay in acinar c ell maturation has been postulated to prevent expression of cellular antigens at the critical time of self tolerance, resulting in inefficient clonal deletion of acinar tissue reactive T cells. In contrast to the role of IFN both prior to and during dev elopment of SS IL 4 appears to be essential during development of adaptive immunity and subsequent onset of glandular dysfunction. Specifically, IL 4 was shown to be necessary for proper isotypic switching, regulating B lymphocyte synthesis of pathogenic IgG1 anti muscarinic acetylcholine type III receptor (M3R) autoantibodies [6, 7] Although these earlier studies have implicated both T H 1 and T H 2 cell associated functions in the development and onset of clinica l SS recent identification of the CD4 + T H 17 memory cells within the lymphocytic focus (LF) of lacrimal and salivary glands of SS s C57BL/6.NOD Aec1Aec2 mice, as well as minor salivary glands of human SS patients, greatly expands the potential complexity in deciphering the autoimmune response underlying SS [8, 9] The T H 17 cell population, while clearly a subset of CD4 + memory effector T cells, appears to be

PAGE 4

4 distinct from, and unrelated to, either the T H 1 or T H 2 cell lineages [10 14] T H 17 effector cells secrete at least one of the six cytokines belonging to the IL 17 family, i.e., IL 17 A, IL 17 B, IL 17 C, IL 17 D, IL 25 and/or IL 17 F ; however, IL 17 A the signature cytokine, ha s received the greatest attention in studies of autoimmune diseases [15] The IL17 cytokines are potent pro inflammatory molecules, actively involved in tissue in flammation via induction of pro inflammatory cytoki ne and chemokine expressions [16] In addition, IL 17 is involved in the mobilization, maturation and migration of neutrophils via the release of IL 8 at the site of injury [17] Interestingly, IL 17A is known to regulate Foxp3+ T Reg cells and vice versa [18] While T H 17 cells have been implicat ed in several autoimmune diseases (e.g., Crohn's disease [19, 20] experimental autoimmune encephalomyelitis (EAE) [21] collagen induced arthritis CIA) [21] SS [8] and others [2, 3] ), this characteristic may require signaling from T H 1 cells already present in the lesion [3] In any event, recent observational studies in SS patients and animal models of primary SS have identified the presence of IL 17 A and its activating cytokine IL 23 in the lymphocytic infiltrates of the exocrine glands, as well as higher levels of circulating IL 1 7 A in both sera and saliva [8] raising the question of the importance of IL 17 in SS Thus, the goals of the present study were to determine whether IL 17A can directly influence the pathology leading to the onset of SS like diseas e by administrati ng exogenous IL 17A to the salivary glands at specific time points

PAGE 5

5 MATERIALS AND METHODS Animals SS non susceptible C57BL/6J mice were bred and maintained under specific pathogen free conditions. The animals were maintained on a 12 hr light dark schedule and provided food and acidified water ad libitum At times indicated in the text, mice were euthanized by cervical dislocation following deep anesthetization with isoflurane, after which organs were freshly explanted for analyses. Bo th the breeding and use of these animals for the present studies were approved by the University of Florida's IACUC and IBC. Sali vary glands of mice were cannulated with mouse IL 17A expressing Ad5 IL17A vector using retrograde injections at either 7 week s ( wks ) of age (n=11) or 16 wks of age (n=8). In addition, mice at 6 wks (n=4) and 15 wks (n=4) were randomly selected and used as pre treated or baseline analysis. Age and sex matched control C57BL/6J mice (n=10 per age group) received the Ad5 LacZ con trol vector using the same protocols. Production of Ad5 LacZ and Ad5 IL17A vectors The recombinant adenovirus vector s used in this study w ere generously provided by Dr. Jay K. Kolls ( Children's Hospital of Pittsburgh Pittsburgh, PA). These vectors are based on the first generation adenovirus serotype 5 (Ad5 ) and shown to produce their appropriate and functional mouse IL 17A and LacZ products [22 24] To obtain sufficient viral vectors for the present studies, ea ch recombinant vector was amplified in HEK293 cells, purified by two rounds of CsCl gradient centrifugation, then dialyzed against 100 mM Tris HCl (pH 7.4), 10 mM MgCl 2 and 10% (v/v) glycerol, as described elsewhere [25] Retrograde salivary gland cannulation of Ad5 LacZ or Ad5 IL17A vectors Previous studies have demonstrated that retrograde salivary gland cannulation is an effective method to direct local gene expression in the salivary glands [26 28] In brief, prior to cannulation, each mouse was anesthetized with a ketamine:xylazine mixture ( 100 mg/mL, 1

PAGE 6

6 mL/kg body weight; Fort Dodge An imal Health, Fort Dodge, IA ) and xylazine (20 mg/mL, 0.7 mL/kg body weight; Phoenix Scientific, St. Joseph, MO ) ) via intramuscularly. Stretched PE 10 polyethylene tubes were inserted into each of the two openings of the salivary ducts. After securing the cannulas, the mouse received an intramuscular injection of atropine (1 mg/kg), followed 10 minutes later by a slow, steady injection of viral vector. Each salivary gland received 50 "l of vector sol ution containing 10 7 viral particles). The cannulas were removed 5 minutes lat er to ensure successful cannulation Measurement of saliva flow To measure stimulated saliva flow individual non anesthetized mice were weighed and given an i.p. injection of 100 l of PBS containing isoproterenol (0.02 mg/ml) and pilocarpine (0.05 mg/ml). Saliva was collected for 10 min from the oral cavity of individual mice using a micropipette starting 1 min after injection of the secretagogue. The volume of each saliva sa mple was measured. Prior to vector cannulation and again at each time point designated in the text, saliva and sera were collected from each mouse. Samples were stored at 80 o C until analyzed. Determination of cytokines levels: Measurements of IL 6 and IL 17A cytokine levels in sera samples were performed by an independent contractor (Millipore, Billerica, MA ) using Luminex¨ platform Intracellular cytokine staining and flow cytometric analysis S pleens were freshly explanted, gently minced through stai nless steel sieves, suspended in phosphate buffered saline (PBS) and centrifuged (1200rpm for 5 minutes). Erythrocytes were lysed by 7 minute incubation in 0.84% NH4Cl. The resulting leukocyte suspensions were washed two times in PBS, counted and resuspend ed inculture media (RPMI 1640 medium, 10% FBS, 2 mM L glutamine, 0.05 mM # mercaptoethanol) at a density of 2 x 10 6 cells/ml. One million cells were pipetted to individual wells of a 24 well microtiter plate pre coated with anti CD3 (10 g/ml) and anti CD2 8 antibodies (2 g/ml) for T cell activation. Cells were incubated for 5 hrs with Leukocyte Activation Cocktail containing GolgiPlug (2 l/ml). Collected cells were

PAGE 7

7 fixed and permeabilized using Cytofix/CytopermFixation/Permeabilization. Flow cytometric ac quisition for intracellular staining was performed following staining with PE Cy5 conjugated anti mouse CD4, FITC conjugated anti IFN and PE conjugated anti IL 17A A. The cells were counted on a FACSCalibur (BD Franklin Lakes, NJ ) and analyzed by FCS Exp ress (De Novo Software Los Angeles, CA ). Histology Following euthanasia, whole salivary glands containing submandibular, sublingual, and parotid glands were surgically removed from each mouse and placed in 10% phosphate buffered formalin for 24 hrs. Fixe d tissues were embedded in paraffin and sectioned at 5 m thickness. Paraffin embedded sections were de paraffinized by immersing in xylene, followed by dehydrating in ethanol. The tissue sections were prepared and stained with hematoxylin and eosin ( H&E ) dye. Stained sections were observed under a microscope for glandular structure and leukocyte infiltration determination. A double blinded procedure was used to enumerate leukocytic infiltrations (lymphocytic foci) in the histological sections of saliva ry glands. Lymphocytic foci (LF) were defined as aggregates of >50 leukocytes quantified per each histological section. Calculations were based on one histological section per mouse. Immunofluorescent staining for CD3+T cells and B220+B cells Histolog ical sections of salivary gland s were incubated with rat anti mouse B220 (BD Pharmi ngen, San Jose, CA) and goat anti mouse CD3 (Santa Cruz Biotechnology, Santa Cruz, CA), followed by incubation with Texas Red conjugated rabbit anti rat IgG (Biomed a, Foste r City, CA) and FITC conjugated rabbit anti goat IgG (Sigma Aldrich, St. Lo uis, MO). The slides were mounted with DAPI mounting medium (Vector Laboratories, Burlingame, CA) Sections were observed at 200X magnification using a Zeiss Axiovert 200M microsco pe.and images were obtained with AxioVs40 software (Ver. 4.7.1.0, Zeiss) (Carl Zeiss, Thornwood, Enumeration of B T cells and total number of nuclei in the LF were performed using Mayachitra imago software (Mayachitra, Inc, Santa Barbara, CA)

PAGE 8

8 Immunohis tochemical staining for IL17 A in salivary glands Immunohistochemical staining for IL17A were carried out as previously described [8] In brief, p araffin embedded salivary glands were deparaffinized by immersion in xylene, followed by antigen retrieval with 10 m M citrate buffer, pH 6.0 Tissue sections were incuba ted overnight at 4¡C with anti IL 17 A antibody (Santa Cruz Biotechnology Santa Cruz, CA). Isotyp e controls were done with rabbit IgG The slides were incubated with biotinyl ated goat anti rabbit IgG followed by horseradish peroxidase conjugated strepavidin incubation using the Vectastain ABC kit. The staining was developed by using diaminobenzidine substrate (Vector Laboratories, Burlingame, CA ), and counterstaining was perfo rmed with hematoxylin. Sections were observed at 200X magnification using a Zeiss Axiovert 200M microscope. And images were obtained with AxioVs40 software (Ver. 4.7.1.0, Zeiss) (Carl Zeiss, Thornwood). Enumeration of IL17 A positive cells was performed o n the entire histological sections of the whole salivary glands using Mayachitra imago software (Mayachitra, Inc, Santa Barbara, CA) although lymphocytic infiltrations are normally seen only in the submandibular glands. Detection of antinuclear antibo dies (ANA ) in the sera ANA in the sera of mice were detected using HEp 2 ANA kit (INOVA Diagnostics, Inc, San Diego, CA). All procedures were performed per manufacturer's instructions. In brief, HEp 2 fixed substrate slides were overlaid with appropri ate mouse sera diluted 1:40, 1:80 and 1:160. Slides were incubated for 1 hr at room temperature in a humidified chamber. After three washes for five minutes with PBS, the substrate slides were covered with Alexa 488 conjugated goat anti mouse IgG (H/L) ( Invitrogen Inc, Carlsbad, CA) diluted 1:100 for 45 min at room temperature. After three washes, fluorescence was detected by fluorescence microscopy at 200X magnification using a Zeiss Axiovert 200M microscope and all images were obtained with AxioVs40 so ftware with constant exposure of 0.3 seconds (Carl Zeiss, Thornwood, NY).

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9 Negative control s are secondary antibody only and positive control s are standard serum with nuclear speckled pattern provided with the kits D ata presented in the results are from slides using 1:40 dilutions of sera from each experimental group. Statistical analyses Statistical evaluat ions were determined by using Mann Whitney U test generated by the GraphPad InStat software ( GraphPad Software La Jolla, CA) The two tailed p val ue <0.05 w as considered significant.

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10 RESULTS Induction of IL 17A and IL 6 cytokine levels in sera following transduction with Ad5 IL17A vector Adenoviral vectors have been reported to show peak gene expressions around day 5 post infusion which then persist for approximately 2 wks [29] In the current study i mmunohistochemi cal s taining for the presence of Lac Z protein in the infused salivary glands demonstrate d that optimal transduction efficiency was approximately 26 5% at 2 wks post infusion which decreased to 15 3% by 9 wks post infusion The cells within the salivary gla nds positive for LacZ expression were predominantly ductal cells, as expected, and acinar cells (data not shown) indicating the virus was capable of passing through the ducts. To determine if transduction of salivary glands with IL 17A alters the serum cytokine profiles, serum preparations were assessed for temporal changes in pro inflammatory cytokine levels. S era of treate d mice were collected at days 5 and 12 post treatment to determine the efficacy of the IL 17A expressing viral vectors to affect cy tokine secretions. As shown in Figure 1 C57BL/6J mice treated with the Ad5 IL17A vector at 10 7 viral particles per salivary gland exhibited a marked increase in the level s of serum IL 17A compared to baseline levels or with C57BL/6J mice receiving the co ntrol Ad5 LacZ vector at 10 7 viral particles per salivary gland demonstrating the efficacy of this viral vector to produce IL 17A In addition, Ad5 IL17A treated C57BL/6J mice also secr eted elevated amount s of the IL 17A related cytokine IL 6 following c annulation Thus, the vectors gain access into the glands and apparently secrete IL 17A in quantities that elevate systemic levels. Increas e d number s of IL 17A producing CD4+ T cells in the spleens of Ad5 IL17A transduc ed mice

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11 As mentioned previo usly, s alivary glands were cannulated with Ad5 IL17A vector at either 7 wks or 16 wks of age. T he time points chosen are based on extensive studies of the development and onset of disease in our C57BL/6.NOD Aec1Aec2 mouse model of S S [1 3, 30, 31] The two time points selected represent the innate and adaptive immune response phases, respectively, in the disease mode l, thus they were chosen to mimic these changes in the parental C57 BL/6 mouse. Microarray analyses examined the temporal differential gene expression of salivary and lacrimal glands of C57BL/6 mice revealed gradual change in pathophysiological related genes from 16 20 wks of age, concomitantly, leukocyte infiltration in the exocrine glands is often obse rved at these age s [32, 33] Thus, it is important to examine the role of I L17 A in the development of SS at prior and post to any pathophysiological changes. Mice treated with Ad5 IL17A or Ad5 LacZ at either 7 w ks or 16 wks of age were euthanized at 26 and 27 wks of age i.e. 19 wks and 11 wks post treatment, respectively S plenocytes were isolated from individual mice and examined for the number of IFN and IL 17A secreting CD4+T cells. Representative data, presented in Figures 2 B & C revealed that the number of IL 17A secreting CD4+T cells in the spleens of mice receiving the Ad5 IL17A vector at 7 wks of age was approximately 2 fold higher than m ice receiving the control Ad5 LacZ vector, while the number of IFN secreting CD4+T cells was approximately half at time of analysis. Similarly, the number of IL 17A secreting CD4+T cells in the spleens of mice receiving the Ad5 IL17A vector at 16 wks of age was approximately 7 fold higher than mice receiving the control Ad5 LacZ vector, while the number of IFN secreting CD4+T cells was less than 50% at time of analysis ( Figure 2E & F ). Results of a similar analysis with untreated mice performed one wk prior to vector cannulations are presented in Figures 2A & D Th ese data suggest that even though the Ad5 vector is considered local ly restricted the effect i n C57BL/6 J mice appeared systematic More importantly, the systemic effect s of IL17A in Ad5 ap pears to be correlate with the duration of gene expression after vector cannulation as evidenced by the 2 fold increase in the level s of IL 17A secreting cells at 19 wks post treatment in younger mice but

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12 a 7 fold increase at 11 wks post treatment in the o ld er group. However, one cannot rule out the possibility that different efficacies are achieved based on the status of disease development in different ages of mice. Induction of SS immune pathology in C57BL/6 mice following treatment with Ad5 IL17A vect or Lymphocyte i nfiltration of the salivary and/or lacrimal glands is a critical criterion for identification of the autoimmune phase of S S in both human and animal models. Although the number of LF present in the salivary and lacrimal glands does not ofte n correlate directly with disease or its severity S S patients and NOD derived mouse strains exhibiting SS like disease typically have lymphocytic infiltrates in their salivary glands IL 17A appears to play a critical role in the development of LF and ha s recently been found to be present within LF in both SS patients and animal models [8] Salivary glands of C57BL/6J mice following cannulation with Ad5 IL17A vector were examined for the presence of infiltrating leukocytes S alivar y glands retrieved from C57BL/6J mice treated with Ad5 LacZ vector at either 7 or 16 wks of age revealed that 10% (1 of 10) in each group had evidence of glandular infiltrations ( Figure 3A, B, G, H, Table 1 ). This observation is consistent with the numbe r of healthy, untreated C57BL/6J mice expected to have infiltration of the salivary glands [8] In contrast, salivary glands from C57BL/6J mice treated with Ad5 IL17A vector at 7 wks of age showed infiltrations in 91% (10 of 11 ) with the mean LF per histological section numbering 4 + 1.32 while salivary glands from C57BL/6J mice treated with Ad5 IL17A vector at 16 wks of age revealed infiltrations in 75% (6 of 8) with a mean LF number per histological section of 2 + 0.83 ( Table 1 ) Besides the number of LF detected in the salivary glands of the experimental animals, i mmunofluorescent staining to detect B and T cells revealed further differences in the cellular composition of the infiltrations betwe en mice administered Ad5 IL17A at a n early or late stage At time of euthanasia, C57BL/6J mice treated with Ad5 IL17A vector at 7 wks of age generally

PAGE 13

13 exhibited smaller foci containing fewer IL 17 positive cells compared to mice receiving the vector at 16 wks of age ( Figure 3 C F & I L ) Consistent with previous observation, the smaller foci in mice treated at 7 wks of age may have resulted from the longer duration of time after cannulation (19 wks) reflecting the decrease s in IL 17A serum levels and IL 17 A positive cell numbers. Detail ed examination of IL 17A positive cells revealed that a majority of IL 17A cells are present in the LF and ductal cells with smaller percentage of positive cells found in the epithelium and acinar cells. Nevertheless, these data support the concept that f ormation and maintenance of LF are due, in part, to the expression levels of IL17 A in the salivary glands. Changes in ANA profiles following instillation of the Ad5 IL 17A vector With the appearance of B and T lymphocytes within the salivary glands of A d5 IL17A treated C57BL/6 mice, plus the significant changes within their splenic T H 17 and T H 1 cell population s the presence of circul ating autoantibodies, specifically ANA detectable by staining of HEp 2 cells was examined To identify the pr esence of A NA the sera prepared from blood samples collected from each C57BL/6J mouse both pre and post cannulation were tested for reactivity on HEp 2 cells. As presented in Figure 4 A the sera collected from C57BL/6J mice at 6 wks of age or one wk prior to vecto r treatment showed a general weak ly diffused cytoplasmic and nuclear background staining of the individual target cells. However, sera collected 19 wks post treatment from mice treated with Ad5 IL17A vector at 7 wks of age showed no cytoplasmic staining wi th course speckled staining and negative nucleoli while Ad5 LacZ treated mice exhibited diffused cytoplasmic staining, weak but fine speckled nucleoplasmic staining with negative nucleoli ( Figure s 4 B & C ) Similar result s w ere seen in C7BL/6J mice whose salivary glands were transduced with Ad5 IL17A vector at 16 wks of age in which the pattern was pronounced course speckled staining with no cytoplasmic staining and negative nucleoli at 29 wks of age or 11 wks post treatment ( Figure s 4 D F ). Considering t he functions of IL 17A, it is interesting to see a gradual and subtle change in ANA profile from diffused cytoplasmic/nuclear

PAGE 14

14 pattern to a distinct course nuclear speckled pattern suggesting influence of IL 17A on the B cells repertoire. Induction of salivary gland dysfunction in C57BL/6 J mice following cannulation wit h Ad5 IL17A vector To determine if the expression of exogenous IL 17A can induce salivary gland dysfunction, s aliva volumes for each mouse were measured at 1 wk prior to treatment then at 3 5 wk intervals post cannulation. C57BL/6J mice that received control Ad5 LacZ vector at 7 wks of age exhibited stable stimulated saliva volume s at 7 wks post treatment with a statistically non significant increase in saliva volumes at 11 wks post t reatment. Nevertheless, C57BL/6J mice whose salivary glands were cannulated at 7 wks of age with Ad5 IL17A exhibited a significant and relatively rapid decrease in stimulated saliva volumes that was most pronounced at 7 wks post treatment, and this observ ation is seen even if the saliva volumes are converted to saliva flow rates based on weights of the mice. After 7 wks post treatment, these mice showed a slight recovery ( Figure 5A ) Similar results were observed with C57BL/6J mice cannulated at 16 wks of age with Ad5 LacZ and Ad5 IL17A vectors ; however, no saliva volume recovery was observed at time of euthanization (i.e., 11 wks post treatment) ( Figure 5B ) Whether a reversal of this inhibition would occur in these older animals will require further studies. Thus, saliva secretions of mice receiving the Ad5 IL17A vector were significantly decreased 1 2 months post treatment when compared to secretions of mice receiving the Ad5 LacZ vector.

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15 DISCUSSION The T H 17 derived IL 17A cytokine is a poten t inflammatory cytokine that has been implicated in a growing list of autoimmune diseases, e.g., multiple sclerosis, Crohn's disease, rheumatoid arthritis psoriasis, systemic lupus eryth ematosus, and SS as well as autoimmunity in animal models [3] As the T H 17/ IL 17A system is considered to be an important factor in innate immunity that, in turn, regulates development of the adaptive immune response, it is not surprising that environmental microflora trigger IL 17 A response s [34] The c onsequence of T H 17/ IL 17A activation includes, in addition to the production the IL 17A family of cyto kines, the production of IL 21, IL 22, chemokines ( MIP 2, CXCL1 CXCL2, CXCL5 ), a nd matrix metalloproteases ( MMP3 and MMP 13 ) [16] all actively involved in tissue inflammation. Interaction of the IL 17A with its receptors evokes activation of IL 8, resulting in recruitment of neutrophils to the site of injury. However the relationship between such early innate/inflammatory events mediated by the T H 17/ IL 17A system and the role T H 17 cells play in subsequent autoimmunity remains unknown, especially in light of the multiple functions now associated with the T H 17 cell pop ulations. Thus, in the present stu dy, we have attempted to elucidate the importanc e of the cytokine IL 17A per se in the development of SS and whether its function may be dependent on when it is expressed. Results in which SS non susceptible C57BL/6J mice were cannulated with the Ad5 IL17A vector revealed that increased IL 17A expression could induce several pathological features of SS irrespective of whether the mice received the vector at 7 or 16 wks of age two time points corresponding to innate and a daptive immune responses in SS susceptible C57BL/6.NOD Aec1Aec2 mice This was noted by decreases in saliva production compared to control vector, elevated production of spe cific pro inflammatory cytokine s detected in ser a, change s in the weak cytoplasmic /nuclear ANA pattern s to nuclear specked staining on HEp2 cells and increased numbers of LF and IL17A positive cells present in the salivary glands at

PAGE 16

16 time of euthanasia. Interestingly, mice received Ad5 IL17A at 7 wks of age showed a slight recovery of s aliva secretion at 7 wks of treatment in contrast to mice received Ad5 IL17A at 16 wks of age. This observation might be supported by the differential immunological or biological response of mice at different ages and the effect of Ad5 IL17A exerted on th e mice. Previous studies have indicated that genes placed within Ad5 vectors are generally expressed transiently and locally restricted ( i.e., 7 14 days) [29] T he present study demonstrates that a rapid and significant increase in the levels of plasma IL 17A was affected at 12 days post cannulation by the Ad5 IL17A transgene vector. Interestingly, this systemic increase in IL17 cytokine levels correlated with significant increases in splenic IL 17A secreting CD4+T cells that persisted at least 19 wks for mice treated at 7 wks of age and 11 wks for mice treated at 16 wks of age. Thes e observations indicated that the Ad5 vector effect was longer than anticipated. Whether this effect might be due to an indirect secondary effect of the Ad5 IL17 vector is unknown. In addition, the systemic increase in IL17A production by local treatment of Ad5 IL17A presented in this study is consistent with previous studies by Bruce Baum's laboratory [35 38] Adesanya et al. [39] has demonstrated that acinar cells can be punctured by retrograde salivary gland cannulati on at a certain vector dosage. The injured acinar cells which have compromise d mucosal barrier integrity allow for leakage of the vector systemically. Further studies by Kagami et al. [37] and He et al. [40] provide d evidence that ductal cannulation of salivary glands can also have systemic effects due to the secretory nature of the salivary glands wh ich are well endowed with protein synthesis organelles and secretory machinery. Nevertheless, these observations are consistent with the concept that SS develops along specific biological processes in a sequential fashion and interference with this proc ess alters development of disease [1 3] Therefore, this study clearly indicates the pathogenic nature of IL 17A in inducing SS like phenotypes when cannulated in the salivary glands.

PAGE 17

17 Previous data have shown t hat lymphocytic infiltrates in the salivary glands secret ing IL 17A and its related cytokines are more important in local glandular destruction. Staining salivary glands for IL 17A revealed that C57BL/6 J mice receiv ing Ad5 IL17A vector not only expressed significant level s of IL 17A but that IL 17A levels correlated with recruitment of inflammatory cells, specifically B and T cells, to the glands This observation is important in light of the recent study suggest ing IL 17A is a critical factor in the ada ptive immune response by inducing the formation of germinal centers for the production of autoreactive antibodies [24] A utoantibodies represent a major component in the onset of SS thus the change s in the ANA pro files observed with sera of C57BL/6J mice cannulated with the Ad5 IL17A vector indicate that IL 17A affects even the B cell compartment in SS non susceptible mice T he presence of LF and loss of saliva secretion raise s an interesting question about the po ssible role of IL 17A in B cell activation. As BAFF is capable of inducing T H 17 cell differentiation in addition to regulating B cell activation [41] t he possible role of BAFF and IL17A in this phenomenon needs to be better defined in SS pathogenesis

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18 CONCLUSIONS The capability of IL 17A to induce features of SS in SS non susceptible mice demonstrates the major role this cytokine plays in the development, a nd possibly onset, of the autoimmune process. How this on e cytokine affects the various features of autoimmunity, and at what level or time point, will require additional studies. More importantly, the study demonstrates that IL 17A might be a potential therapeutic target for SS.

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19 LIST OF ABBREVATIONS SS: Sjš gren's Syndrome, IL: Interleukin, Ad5: Adenovirus serotype 5, IFN : Interferon EAE: Experimental autoimmune encephalomyelitis, CIA: Collagen induced arthritis, LF: Lymphocytic Focus, ANA: Antinuclear antibodies, MIP 2: Macrophage inflammatory protein 2, CXCL1: Chemokine (C X C motif) ligand, MMP: matrix metall oproteases, BAFF: B cell activating factor.

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20 COMPETING INTERESTS The authors declare no conflicts of interest.

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21 AUTHORS' CONTRIBUTIO NS JAC produced and determined the titers of the Ad5 LacZ and Ad5 IL17A viral vectors. HY and BL pe rformed retrograde ductal cannulations/instillations of the vectors into the salivary glands. CQN designed the study, performed saliva flow, flow cytometry, histology and statistical analyses, and prepared the manuscript. WC carried out the ANA staining. ABP assisted in the manuscript preparation. All authors read and approved the final manuscript.

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22 ACKNOWLEDGEMENTS The authors would like to thank Dr. Jay K. Kolls and Dr. Julie Bindas (Children's Hospital of Pittsburgh) for generousl y providing the Ad5 LacZ and Ad5 IL17A vectors and Dr. Phil Cohen for his critical reading of the manuscript and helpful suggestions. We greatly appreciate the assistance of Dr. Craig Meyers and Dr. Nicholas Muzyczka for the use of the microscope. Publication of this ar ticle was funded in part by the University of Florida Open Access publishing Fund

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23 FUNDING This work was supported by PHS grants K99DE018958 (CQN) from NIDCR, R21AI081952 (ABP) from NIAID and funds from the Sjšgren's Sy ndrome Foundation and Center for O rphan Autoimmune Disorders HY and JAC were supported by an NIH, NIDCR intramural research grant.

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24 REFERENCES 1. Nguyen CQ, Cha SR, Peck AB: Sjšgren's syndrome (SjS) like disease of mice: the importance of B lymphocytes and au toantibodies Frontiers in Bioscience 2007, 12 :1767 1789. 2. Nguyen CQ, Peck AB: Unraveling the pathophysiology of Sjogren syndrome associated dry eye disease Ocul Surf 2009, 7 :11 27. 3. Lee BH, Tudares MA, Nguyen CQ: Sjogren's syndrome: an old tale with a new twist Arch Immunol Ther Exp (Warsz) 2009, 57 :57 66. 4. Brayer JB, Cha S, Nagashima H, Yasunari U, Lindberg A, Diggs S, Martinez J, Goa J, Humphreys Beher MG, Peck AB: IL 4 dependent effector phase in autoimmune exocrinopathy as defined by the NOD.IL 4 gene knockout mouse model of Sjogren's syndrome Scand J Immunol 2001, 54 :133 140. 5. Cha S, Brayer J, Gao J, Brown V, Killedar S, Yasunari U, Peck AB: A dual role for interferon gamma in the pathogenesis of Sjogren's syndrome like autoimmune exocrinopa thy in the nonobese diabetic mouse Scand J Immunol 2004, 60 :552 565. 6. Nguyen KH, Brayer J, Cha S, Diggs S, Yasunari U, Hilal G, Peck AB, Humphreys Beher MG: Evidence for antimuscarinic acetylcholine receptor antibody mediated secretory dysfunction in no d mice Arthritis Rheum 2000, 43 :2297 2306. 7. Nguyen CQ, Gao JH, Kim H, Saban DR, Cornelius JG, Peck AB: IL 4 STAT6 signal transduction dependent induction of the clinical phase of Sjogren's syndrome like disease of the nonobese diabetic mouse J Immunol 2007, 179 :382 390. 8. Nguyen CQ, Hu MH, Li Y, Stewart C, Peck AB: Salivary gland tissue expression of interleukin 23 and interleukin 17 in Sjogren's syndrome: Findings in humans and mice Arthritis Rheum 2008, 58 :734 743.

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29 40. He X, Goldsmith CM, Marmary Y, Wellner RB, Parlow AF, Nieman LK, Baum BJ: Systemic action of human growth hormone following adenovirus mediated gene transfer to rat submandibular glands Gene Ther 1998, 5 :537 541. 41. Doreau A, Belot A, Bastid J, Riche B, Trescol Biemont MC, Ranchin B, Fabien N, Cochat P, Pouteil Noble C, Trolliet P et al : Interleukin 17 acts in synergy with B cell activating fact or to influence B cell biology and the pathophysiology of systemic lupus erythematosus Nat Immunol 2009, 10 :778 785.

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30 FIGURE LEGENDS: Figure 1. Rapid changes in IL 17A and IL 6 serum cytokine concentrations in C57BL/6J mice following vector cannulat ions. Sera were prepared from blood collected from individual 5 wk old mice (n=4) randomly chosen 1 wk prior to vector treatment (day 0 on the graph). Mice were allowed to acclimate for 7 days, followed by vector instillation of each salivary gland with 50 l of vector solution containing 10 7 viral particles of either Ad5 LacZ or Ad5 IL17A vector. Sera were again prepared from blood collected from individual mice (n=11) at day 5 and day 12 post treatment. Concentrations of cytokines were determined usin g the Luminex platform. To ensure sufficient quantities for testing, the sera of three individual mice of each experimental group were pooled. ND: not detected indicates levels below threshold detection. Figure 2 Intracellular staining for IL 17A an d IFN secreting CD4 + T cells in spleens of Ad5 I L17A treated mice Splenic leukocytes prepared from C57BL/6J mice (n=4) at 6 wks of age (one wk prior to vector treatment) and 26 wks old (19 wks post vector treatment), considered early treatment ( A C ), or splenic leukocytes prepared from C57BL/6J mice (n=4) at 15 wks of age (one wk prior to vector treatment) and 27 wks old (11 wks post vector treatment), considered late treatment ( D F ) were examined for the presence of intracellular IL 17A and IFN gated on CD4 + T cells following a 5 hr in vitro activation with anti CD3$ and anti CD28 in Leukocyte Activation Cocktail containing GolgiPlug. Flow cytometric acquisition was performed by staining with PE Cy5 conjugated rat anti CD4, FITC conjugated rat anti IFN! and/or PE conjugated rat anti IL 17A. Data was analyzed by FCS Express. Flow cytometric images shown are from one representative analysis of 2 independent experiments that examined 2 different mice within each exper iment. Data presented as mean + SEM for n=4 per group and statistical analyses were performed comparing the means of the Ad LacZ and Ad IL17A treated groups at

PAGE 31

31 26 wks and 27 wks of early and late treatment, respectively. (*) indicates p<0.5 using Mann Wh itney U test. Figure 3 Histological examination of salivary glands Salivary gland histology was examined at 19 wks post vector infusions of mice treated at 7 wks of age (early treatment) or at 11 wks post vector infusions of mice treated at 16 wks of age (late treatment). Panels show representative H&E staining of salivary gland tissue from mice receiving early treatment with Ad5 LacZ (n=10) ( A ), or Ad5 IL17A (n=11) ( B ); fl uorescent staining and enumeration of B and T cells in Ad5 IL17 A treated mice ( C & D ) and immunohistochemical staining and enumeration of IL 17 A positive cells in Ad5 IL17 A treated mice ( E & F ) ; H&E staining of s alivary gland tissue from mice receiving late treatment with Ad5 LacZ ( n=10 ) ( G ), or Ad5 IL17 ( n=8) ( H ); and fluorescent staining and enumeration of B and T cells in Ad5 IL17 A treated mice ( I & J ) and immunohistochemical staining and enumeration of IL 17 A positive cells in Ad5 IL17 A treated mice ( K & L ). Black arrows indicate representative lymphocytic infiltrate. Figure 4 Identification of the antinuclear antibodies in sera of C57BL/6J mice Representative patterns of cellular staining of HEp 2 cells by sera diluted at 1:40 prepared from sera taken from C57BL/6 mice cannulated with Ad5 LacZ or Ad5 IL17A vectors at 7 wks of age with pre treated mice (baseline) at 6 wks of age (n=4) ( A C ), and cannulated at16 wks of age with Ad5 LacZ or Ad5 IL17A and pre treated mice (baseline) at 15 wks of age (n=4) ( D F ) with negative control using secondary antibody only ( G) and positive control with standard nuclear speckled serum ( H) Representative patterns were determined with n=4 for two baselines and n=7 for each time point presented in the figure. Fixed HEp 2 substrate slides were incubated with individual mouse sera diluted 1:40 1:80 and 1:160 followed by development with FITC conjugated goat anti mouse IgG. Fluorescent patterns were detected by fluorescence microscopy at 400X magnification.

PAGE 32

32 Figure 5. S timulated s aliva flow in treated C57BL/6 J mice One week prior to saliva ry gland cannulations with either Ad5 LacZ or Ad5 IL17A vector, stimulated saliva volume s w ere determined for individual mice within each of the four experimental groups: early treatment with Ad5 LacZ (n=10) or Ad5 IL17A (n=11) at 7 wks of age ( A ) or late treatment with Ad5 Lac Z (n=10) or Ad5 IL17A (n=8) at 16 wks of age ( B ). Saliva was collected every 3 5 wks post treatment until the mice were euthanized. Statistical analysis was used to determine the significance between the Ad5 LacZ and Ad5 IL17A trea ted mice at each time point. (NS: not significant, p=*<0.05, p=**<0.01 p=***<0.001 ) Arrows indicate the initial time point of vector cannulation

PAGE 33

33 Table 1: Quantification of lymphocytic foci (LF) in salivary glands Ad5:LacZ Ad5:IL17A No LF LF Mea n LF No LF LF Mean LF Early 9 a (90%) b 1 (10%) 1 1 (9%) 10 (91%) 4 + 1.32 c Late 9 (90%) 1 (10%) 1 2 (25%) 6 (75%) 2 + 0.83 a number of mice b percentage of mice c mean number of LF + SEM per histological salivary gland section LF; lymphocytic foci, Ad5; Adenovirus serotype 5, IL; interleukin.

PAGE 34

Figure 1

PAGE 35

Figure 2

PAGE 36

Figure 3

PAGE 37

Figure 4

PAGE 38

Figure 5


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String P21_ST00001 236 CONTENT AUTHORS' WC 1.00 CC 00000000
SP P21_SP00001 536 395 18
P21_ST00002 554 378 CONTRIBUTIONS 0.93 0040000000040
P21_TB00002 295 515 1935 474
P21_TL00002 301 521 1912 41
P21_ST00003 83 JAC 0.97 000
P21_SP00002 384 553
P21_ST00004 402 185 produced
P21_SP00003 587 562
P21_ST00005 605 71 and
P21_SP00004 676
P21_ST00006 694 224 determined 0000000000
P21_SP00005 918 17
P21_ST00007 935 61 the
P21_SP00006 996 16
P21_ST00008 1012 96 titers 000000
P21_SP00007 1108
P21_ST00009 1125 37 of 00
P21_SP00008 1162 13
P21_ST00010 1175 60
P21_SP00009 1235 15
P21_ST00011 1250 197 Ad5-LacZ
P21_SP00010 1447
P21_ST00012 1464
P21_SP00011 1535
P21_ST00013 1551 215 Ad5-IL17A 000000000
P21_SP00012 1766
P21_ST00014 1781 80 viral 00000
P21_SP00013 1861
P21_ST00015 1878 522 155 31 vectors.
P21_SP00014 2033 34
P21_ST00016 2067 58 HY
P21_SP00015 2125
P21_ST00017 2142
P21_TL00003 304 626 1915
P21_ST00018 51 BL
P21_SP00016 355 658
P21_ST00019 372 202 performed
P21_SP00017 574 667 19
P21_ST00020 593 206 retrograde
P21_SP00018 799
P21_ST00021 817 117 ductal
P21_SP00019 934
P21_ST00022 952 490 cannulationsinstillations 0.98 00000000000040000000000000
P21_SP00020 1442
P21_ST00023 1459
P21_SP00021 1496 12
P21_ST00024 1508
P21_SP00022 1569
P21_ST00025 1585 627 145 vectors 0000000
P21_SP00023 1730
P21_ST00026 1747 69 into 0000
P21_SP00024 1816
P21_ST00027 1832
P21_SP00025 1892
P21_ST00028 1909 152 salivary
P21_SP00026 2061
P21_ST00029 2078 141 glands.
P21_TL00004 302 732 1768
P21_ST00030 CQN
P21_SP00027 398 766
P21_ST00031 417 180 designed
P21_SP00028 597 773
P21_ST00032 614
P21_SP00029 675 764
P21_ST00033 692 115 study,
P21_SP00030 807
P21_ST00034 828
P21_SP00031 1030
P21_ST00035 1048 113 saliva
P21_SP00032 1161
P21_ST00036 1177 89 39 flow,
P21_SP00033 1266 771
P21_ST00037 1284 81 flow
P21_SP00034 1365 14
P21_ST00038 1379 733 205 40 cytometry,
P21_SP00035 1584
P21_ST00039 1605 176 histology
P21_SP00036
P21_ST00040 1797
P21_SP00037 1868
P21_ST00041 1886 184 statistical 00000000000
P21_TL00005 837 1922
P21_ST00042 187 analyses,
P21_SP00038 489 878
P21_ST00043 508
P21_SP00039 579 869 20
P21_ST00044 599 177 prepared
P21_SP00040 776
P21_ST00045 793
P21_SP00041 853
P21_ST00046 871 229 manuscript.
P21_SP00042 1100
P21_ST00047 1132 73 0.96
P21_SP00043 1205
P21_ST00048 1222 134 carried
P21_SP00044 1356
P21_ST00049 1374 838 out
P21_SP00045 1435
P21_ST00050 1450
P21_SP00046 1510
P21_ST00051 1525 93 ANA
P21_SP00047 1618
P21_ST00052 1634 164 staining.
P21_SP00048 1798
P21_ST00053 1829 ABP
P21_SP00049 1918
P21_ST00054 163 assisted
P21_SP00050 2098
P21_ST00055 2117 29 in
P21_SP00051 2146
P21_ST00056 2163
P21_TL00006 303 942 1536
P21_ST00057 220 manuscript
P21_SP00052 523 983
P21_ST00058 540 237 preparation. 000000000000
P21_SP00053 777 30
P21_ST00059 48 All
P21_SP00054 855 974
P21_ST00060 873 149 authors
P21_SP00055 1022
P21_ST00061 1039 86 read
P21_SP00056
P21_ST00062 1143
P21_SP00057 1214
P21_ST00063 1232 186 approved
P21_SP00058 1418
P21_ST00064
P21_SP00059 1495
P21_ST00065 1512 79 final
P21_SP00060 1591
P21_ST00066 1610
P21_TB00003 1248 3047 49 42
P21_TL00007 1254 3053
P21_ST00067


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sourceImageInformation
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String P3_ST00001 344 32 CONTENT INTRODUCTION WC 0.93 CC 040000000004
SP P3_SP00001 647 395 -195
P3_ST00002 452 468 187 41 Sjogren's 0.99 000000010
P3_SP00002 639 509 17
P3_ST00003 656 197 syndrome 1.00 00000000
P3_SP00003 853 18
P3_ST00004 871 85 (SS) 0000
P3_SP00004 956 19
P3_ST00005 975 28 is 00
P3_SP00005 1003 500
P3_ST00006 1020 476 21 24 a
P3_SP00006 1041
P3_ST00007 1058 154 39 chronic,
P3_SP00007 1212 507
P3_ST00008 1231 177 systemic
P3_SP00008 1408 15
P3_ST00009 1423 247 autoimmune 0000000000
P3_SP00009 1670
P3_ST00010 1688 153 disease 0000000
P3_SP00010 1841
P3_ST00011 1858 270 characterized 0000000000000
P3_SP00011 2128
P3_ST00012 2147 469 96 31 most
P3_TL00002 574 1799
P3_ST00013 143 notably
P3_SP00012 446 615
P3_ST00014 464 43 by
P3_SP00013
P3_ST00015 524 259 development 00000000000
P3_SP00014 783 16
P3_ST00016 799 37 of
P3_SP00015 836 606 14
P3_ST00017 850 60 dry 000
P3_SP00016 910
P3_ST00018 926 582 93 33 eyes
P3_SP00017 1019
P3_ST00019 1036 71 and
P3_SP00018 1107
P3_ST00020 1125
P3_SP00019 1185
P3_ST00021 1202 121 mouth 00000
P3_SP00020 1323
P3_ST00022 1342 manifestations, 000000000000000
P3_SP00021 1643 613 20
P3_ST00023 1663 186 indicative
P3_SP00022 1849
P3_ST00024 1866 38
P3_SP00023 1904 13
P3_ST00025 1917 575 185 40 secretory 000000000
P3_TL00003 302 679 1802
P3_ST00026 226 dysfunction
P3_SP00024 528 720
P3_ST00027 547
P3_SP00025 584 711 12
P3_ST00028 596 61 the
P3_SP00026 657
P3_ST00029 675 152 lacrimal
P3_SP00027 827
P3_ST00030 845
P3_SP00028 916
P3_ST00031 934 151 salivary
P3_SP00029 1085
P3_ST00032 1102 131 glands 000000
P3_SP00030 1233
P3_ST00033 1251 97 [1-3].
P3_SP00031 1348 30
P3_ST00034 1378 Although
P3_SP00032 1555
P3_ST00035 1572
P3_SP00033 1633
P3_ST00036 1650 etiology
P3_SP00034 1804
P3_ST00037 1821
P3_SP00035
P3_ST00038 1872 56 SS 0.98
P3_SP00036 1928
P3_ST00039 1946 158 remains
P3_TL00004 784 1819
P3_ST00040 188 unknown,
P3_SP00037 491 823
P3_ST00041 512 175 intensive
P3_SP00038 687 816
P3_ST00042 705 141 studies
P3_SP00039 846
P3_ST00043 863
P3_SP00040 900
P3_ST00044 914 792 45 an
P3_SP00041 959
P3_ST00045 977 88 ever
P3_SP00042 1065
P3_ST00046 1079 206 expanding
P3_SP00043 1285 825
P3_ST00047 1305 number
P3_SP00044 1458
P3_ST00048 1472
P3_SP00045 1509
P3_ST00049 1523 130 animal
P3_SP00046 1653
P3_ST00050 1671 models
P3_SP00047 1814
P3_ST00051 1832
P3_SP00048 1860
P3_ST00052 1878 192 beginning
P3_SP00049 2070
P3_ST00053 2087 785 35 to
P3_TL00005 890 1868
P3_ST00054 144 unravel
P3_SP00050 447 922
P3_ST00055
P3_SP00051
P3_ST00056 541 genetic,
P3_SP00052 695 931
P3_ST00057 716 196 molecular
P3_SP00053 912
P3_ST00058
P3_SP00054 997
P3_ST00059 1016 287 immunological
P3_SP00055 1303
P3_ST00060 1322 102 basis
P3_SP00056 1424
P3_ST00061 1440 53 for
P3_SP00057 1493
P3_ST00062 1506 68 this
P3_SP00058 1574
P3_ST00063 1591 215 disease[1].
P3_SP00059 1806 34
P3_ST00064 1840 173 Previous
P3_SP00060 2013
P3_ST00065 2029 142
P3_TL00006 995 1894
P3_ST00066 94 have
P3_SP00061 397 1027
P3_ST00067 415 200 implicated
P3_SP00062
P3_ST00068 633 125 critical
P3_SP00063 758
P3_ST00069 777 roles
P3_SP00064
P3_ST00070 887
P3_SP00065 940
P3_ST00071 955 83 both
P3_SP00066 1038
P3_ST00072 1057 227 interferon-y 000000000000
P3_SP00067 1284
P3_ST00073 1302 136 (IFN-y)
P3_SP00068 1438
P3_ST00074 1456 0.90 300
P3_SP00069 1527
P3_ST00075 1546 203 interleukin
P3_SP00070 1749
P3_ST00076 1768 104 (IL)-4
P3_SP00071
P3_ST00077 1890 29 in
P3_SP00072 1919
P3_ST00078 1937 260
P3_TL00007 1101 1843
P3_ST00079
P3_SP00073 373 1133
P3_ST00080 391 110 onset
P3_SP00074 501
P3_ST00081 516
P3_SP00075 554
P3_ST00082 567 SS-like
P3_SP00076 708
P3_ST00083 725
P3_SP00077 878
P3_ST00084 897
P3_SP00078
P3_ST00085 946 168 NODLtJ 0.92 0005000
P3_SP00079 1114
P3_ST00086
P3_SP00080 1204
P3_ST00087 1222 514 C57BL6.NOD-AecfAec2 0.64 0000050000008857888575
P3_SP00081 1736
P3_ST00088 1753 91 mice
P3_SP00082 1844
P3_ST00089 1862 [4,
P3_SP00083 1905 1142
P3_ST00090 1925 44 5],
P3_SP00084 1969
P3_ST00091 1989 156 strongly
P3_TL00008 1206 1865
P3_ST00092 216 suggesting
P3_SP00085 518 1247
P3_ST00093 537 241 involvement
P3_SP00086 778 1238
P3_ST00094 794
P3_SP00087 831
P3_ST00095 844 65 ThI
P3_SP00088 909 1244 23
P3_ST00096 932
P3_SP00089
P3_ST00097 70 Th2
P3_SP00090 1090
P3_ST00098 1109 63 cell
P3_SP00091 1172
P3_ST00099 1191 239 populations,
P3_SP00092 1430
P3_ST00100 1451 respectively.
P3_SP00093 1698
P3_ST00101 1729 111 While
P3_SP00094
P3_ST00102 106 IFN-y
P3_SP00095 1966
P3_ST00103 1983 184 regulates
P3_TL00009 1827 47
P3_ST00104 1311 267 cell-mediated
P3_SP00096 569 1343
P3_ST00105 588 179 immunity
P3_SP00097 767 1352
P3_ST00106 through
P3_SP00098
P3_ST00107 952 activation
P3_SP00099 1140
P3_ST00108 1158
P3_SP00100 1196
P3_ST00109 1210 283 macrophages,
P3_SP00101
P3_ST00110 1514 NK
P3_SP00102 1575
P3_ST00111 1589 cells
P3_SP00103 1677
P3_ST00112 1693
P3_SP00104 1764
P3_ST00113 1782 105 CD8'^ 0.63 000710
P3_SP00105 1887
P3_ST00114 1903 26 T
P3_SP00106 1929
P3_ST00115 1944 98 cells,
P3_SP00107 2042 1350
P3_ST00116 2061
P3_TL00010 1417 1730
P3_ST00117 164 cytokine
P3_SP00108 466
P3_ST00118 483 1425 162 appears
P3_SP00109 645
P3_ST00119 660 1418
P3_SP00110 1449
P3_ST00120 713 219 predispose
P3_SP00111
P3_ST00121 948 109 these
P3_SP00112
P3_ST00122 1074 SS-susceptible 00000000000000
P3_SP00113 1375
P3_ST00123 1393 92
P3_SP00114 1485
P3_ST00124 1503
P3_SP00115
P3_ST00125 1564 retarding
P3_SP00116 1739
P3_ST00126 1757
P3_SP00117 1908
P3_ST00127 107 gland
P3_TL00011 1522
P3_ST00128 307 organogenesis,
P3_SP00118 609 1563
P3_ST00129 628 198 especially
P3_SP00119 826
P3_ST00130 843 233 proliferation
P3_SP00120 1076
P3_ST00131 1094
P3_SP00121 1132 1554
P3_ST00132 1145 124 acinar
P3_SP00122 1269
P3_ST00133 1282 116 tissue
P3_SP00123 1398
P3_ST00134 1416 [5].
P3_SP00124
P3_ST00135 1504 This
P3_SP00125 1587
P3_ST00136 1604 delay
P3_SP00126 1710
P3_ST00137 1727
P3_SP00127 1756
P3_ST00138 1775 123
P3_SP00128 1898
P3_ST00139 1912 64
P3_SP00129 1976
P3_ST00140 1995 210 maturation
P3_TL00012 1628 1773
P3_ST00141 69 has
P3_SP00130 372 1660
P3_ST00142 390 95 been
P3_SP00131 485
P3_ST00143 504 205 postulated
P3_SP00132 709 1669
P3_ST00144 727 1629
P3_SP00133 761
P3_ST00145 779 150 prevent
P3_SP00134 929
P3_ST00146 944 expression
P3_SP00135 1160
P3_ST00147 1178
P3_SP00136 1216
P3_ST00148 1229 cellular
P3_SP00137 1373
P3_ST00149 1387 170 antigens
P3_SP00138 1557
P3_ST00150 1573 36 at
P3_SP00139 1609
P3_ST00151 1623
P3_SP00140 1683
P3_ST00152 1701
P3_SP00141 1825
P3_ST00153 1842 time
P3_SP00142
P3_ST00154 1943
P3_SP00143 1980
P3_ST00155 1994 82 self-
P3_TL00013 1733 1889
P3_ST00156 tolerance,
P3_SP00144 497 1772
P3_ST00157 517 167 resulting
P3_SP00145 684 1774
P3_ST00158 703
P3_SP00146 732 1765
P3_ST00159 752 190 inefficient
P3_SP00147 942
P3_ST00160 957 115 clonal
P3_SP00148 1072
P3_ST00161 155 deletion
P3_SP00149 1245
P3_ST00162 1263
P3_SP00150 1300
P3_ST00163 1314
P3_SP00151 1437
P3_ST00164 1450 292 tissue-reactive
P3_SP00152 1742
P3_ST00165 1758
P3_SP00153 1784
P3_ST00166 1800 cells.
P3_SP00154
P3_ST00167 1932 In
P3_SP00155 1963
P3_ST00168 1981 1734 160 contrast
P3_SP00156 2141
P3_ST00169 2156
P3_TL00014 1838 1942
P3_ST00170
P3_SP00157 361 1870
P3_ST00171 380 role
P3_SP00158 450
P3_ST00172
P3_SP00159 505
P3_ST00173 521
P3_SP00160 627 1879
P3_ST00174 644
P3_SP00161
P3_ST00175 746 90 prior
P3_SP00162
P3_ST00176 849 1839
P3_SP00163 883
P3_ST00177 901
P3_SP00164 972
P3_ST00178 990 122 during
P3_SP00165 1112
P3_ST00179 1130
P3_SP00166 1390
P3_ST00180 1405
P3_SP00167 1443
P3_ST00181 67 SS,
P3_SP00168 1877 22
P3_ST00182 1545 72 IL-4
P3_SP00169 1617
P3_ST00183 1634 1846
P3_SP00170 1796
P3_ST00184 1812
P3_SP00171 1847
P3_ST00185 be
P3_SP00172 1910
P3_ST00186 1927 176 essential
P3_SP00173 2103
P3_ST00187 2121
P3_TL00015 1930
P3_ST00188
P3_SP00174 562 1985
P3_ST00189 577
P3_SP00175
P3_ST00190 169 adaptive
P3_SP00176 797
P3_ST00191 815
P3_SP00177 994
P3_ST00192 1010
P3_SP00178 1081
P3_ST00193 1099 235 subsequent
P3_SP00179 1334
P3_ST00194 1349 1945
P3_SP00180 1459
P3_ST00195 1474
P3_SP00181 1511
P3_ST00196 1525 glandular
P3_SP00182 1712
P3_ST00197 1726 238 dysfunction.
P3_SP00183 1964
P3_ST00198 1996 236 Specifically,
P3_TL00016 304 2049 1741
P3_ST00199
P3_SP00184 376 2081
P3_ST00200 392 2057 79 was
P3_SP00185 471
P3_ST00201 488 127 shown
P3_SP00186
P3_ST00202 632 2050
P3_SP00187 667
P3_ST00203 685 46
P3_SP00188 731
P3_ST00204 749 204 necessary
P3_SP00189 953 2090
P3_ST00205 968 54
P3_SP00190 1022
P3_ST00206 1037 proper
P3_SP00191 1167
P3_ST00207 1182 isotypic
P3_SP00192 1332
P3_ST00208 1346 195 switching,
P3_SP00193 1541
P3_ST00209 1561 regulating
P3_SP00194
P3_ST00210 1776 B
P3_SP00195
P3_ST00211 lymphocyte
P3_TL00017 2155 1656
P3_ST00212 synthesis
P3_SP00196 489 2196
P3_ST00213 506
P3_SP00197 543 2187
P3_ST00214 558 221 pathogenic
P3_SP00198
P3_ST00215 796 87 IgGI
P3_SP00199
P3_ST00216 906 306 anti-muscarinic
P3_SP00200
P3_ST00217 1227 acetylcholine
P3_SP00201 1487
P3_ST00218 type
P3_SP00202
P3_ST00219 1606 III
P3_SP00203 1635
P3_ST00220 166 receptor
P3_SP00204 1822
P3_ST00221 1837 (M3R)
P3_TL00018 2260 419
P3_ST00222 294 autoantibodies
P3_SP00205 2292
P3_ST00223 614 [6,
P3_SP00206 2301
P3_ST00224 677 7].
P3_TL00019 2365 1613
P3_ST00225
P3_SP00207 2406
P3_ST00226 108
P3_SP00208 753 2397
P3_ST00227 771 126 earlier
P3_SP00209
P3_ST00228 911
P3_SP00210 1052
P3_ST00229 1070
P3_SP00211 1163
P3_ST00230
P3_SP00212 1382
P3_ST00231 1401
P3_SP00213 1484
P3_ST00232 1501
P3_SP00214 1566 2403
P3_ST00233
P3_SP00215
P3_ST00234
P3_SP00216 1747
P3_ST00235 1766 297 cell-associated
P3_TL00020 2465 1851
P3_ST00236 2471 181 functions
P3_SP00217 482 2503
P3_ST00237 499
P3_SP00218
P3_ST00238 546
P3_SP00219
P3_ST00239 623
P3_SP00220 2512
P3_ST00240 899
P3_SP00221 970
P3_ST00241 988 2472
P3_SP00222 1097
P3_ST00242 1113
P3_SP00223 1150
P3_ST00243 1164 132 clinical
P3_SP00224 1296
P3_ST00244
P3_SP00225 1381 2510
P3_ST00245 recent
P3_SP00226
P3_ST00246 249 identification
P3_SP00227 1790
P3_ST00247 1808
P3_SP00228 1845
P3_ST00248
P3_SP00229 1918
P3_ST00249 1935 CD4'^
P3_SP00230 2040
P3_ST00250 2056
P3_SP00231 2509 10
P3_ST00251 2131 7
P3_TL00021 2572
P3_ST00252 2584 161 memory
P3_SP00232 2617
P3_ST00253 480 2576
P3_SP00233 568 2608
P3_ST00254 583 113 within
P3_SP00234 696
P3_ST00255 714
P3_SP00235 774
P3_ST00256 237 lymphocytic
P3_SP00236 1029
P3_ST00257 1042 focus
P3_SP00237 1149
P3_ST00258 77 (LF)
P3_SP00238
P3_ST00259 1262
P3_SP00239
P3_ST00260
P3_SP00240 1466
P3_ST00261
P3_SP00241
P3_ST00262
P3_SP00242 1725
P3_ST00263
P3_SP00243
P3_ST00264
P3_SP00244 1926
P3_ST00265 73 SS^ 0.65 0010
P3_TL00022 2682 1907
P3_ST00266 515 C57BL6.NOD-Aec'Aec2 00000400000088476888475
P3_SP00245 817 2714
P3_ST00267 833 mice,
P3_SP00246 935 2721
P3_ST00268 954 2690 as
P3_SP00247 999
P3_ST00269 1013 76 well
P3_SP00248 1089
P3_ST00270
P3_SP00249 1151
P3_ST00271 1169 112 minor
P3_SP00250 1281
P3_ST00272 1295
P3_SP00251 1447 2723
P3_ST00273 1464
P3_SP00252 1595
P3_ST00274 1611
P3_SP00253 1649
P3_ST00275 134 human
P3_SP00254 1797
P3_ST00276 1815 57
P3_SP00255
P3_ST00277 patients,
P3_SP00256
P3_ST00278 2075 greatly
P3_TL00023 2787
P3_ST00279 expands
P3_SP00257 2828
P3_ST00280 487
P3_SP00258 2819
P3_ST00281 565 potential
P3_SP00259 733
P3_ST00282 750 213 complexity
P3_SP00260 963
P3_ST00283 981
P3_SP00261
P3_ST00284 1028 232 deciphering
P3_SP00262 1260
P3_ST00285 1277
P3_SP00263 1337
P3_ST00286 1354 248
P3_SP00264 1602
P3_ST00287 1620 2795 183 response
P3_SP00265 1803
P3_ST00288 underlying
P3_SP00266 2027
P3_ST00289 2045
P3_SP00267 2101
P3_ST00290 2120 [8,
P3_SP00268 2163
P3_ST00291 2182 9].
P3_TL00024 2886 1922
P3_ST00292 2892 75 The
P3_SP00269 2924
P3_ST00293 393
P3_SP00270 458 2930
P3_ST00294
P3_SP00271
P3_ST00295
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P3_ST00297 while
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P3_SP00275 1071
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P3_SP00276 1108
P3_ST00300 1126 subset
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P3_SP00278
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P3_SP00282
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P8_ST00049 2195 627 36 at
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P8_ST00050 74 4C 0.97
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P8_SP00048
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P8_SP00050 1050
P8_ST00055 1067 93 Cruz
P8_SP00051 1160
P8_ST00056 1178 Biotechnology 0000000000000
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P8_ST00057 1477 115 Santa
P8_SP00053 1592
P8_ST00058 1610 102 Cruz,
P8_SP00054 1712 771
P8_ST00059 85 CA).
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P8_ST00061 1997 156 controls
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P8_ST00062 845
P8_SP00057 397
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P8_ST00066 752 IgG.
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P8_SP00062 937
P8_ST00068 954 slides
P8_SP00063 1068
P8_ST00069 1082
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P8_ST00070 1197
P8_SP00065 1390
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P8_ST00073 1747 838 86 40 goat
P8_SP00068
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P8_ST00076
P8_SP00070 465 974
P8_ST00077 484
P8_SP00071 528 983
P8_ST00078 545 233 horseradish
P8_SP00072 778
P8_ST00079 797 peroxidase-conjugated 000000000000000000000
P8_SP00073 1265
P8_ST00080 1283 216 strepavidin
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P8_ST00081 1518 203 incubation
P8_SP00075 1721
P8_ST00082 1740 103 using
P8_SP00076 1843
P8_ST00083 1860 the
P8_SP00077 1921
P8_ST00084 1937 209 Vectastain
P8_TL00008 1048
P8_ST00085 92 ABC
P8_SP00078 392 1080
P8_ST00086 410 51 kit.
P8_SP00079 461
P8_ST00087 479
P8_SP00080 555
P8_ST00088 572 152
P8_SP00081 724 1089
P8_ST00089 741 1056 79 was
P8_SP00082 820
P8_ST00090 206 developed
P8_SP00083 1043
P8_ST00091 1062
P8_SP00084 1106
P8_ST00092 1123
P8_SP00085 1226
P8_ST00093 1245 352 diaminobenzidine 0000000000000000
P8_SP00086 1597
P8_ST00094 1614 184 substrate
P8_SP00087 1798
P8_ST00095 1816 146 (Vector
P8_SP00088
P8_ST00096 1978 259 Laboratories,
P8_TL00009 1153
P8_ST00097 236 Burlingame,
P8_SP00089 540 1194
P8_ST00098 559 CA),
P8_SP00090 644
P8_ST00099 664 71 and
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P8_ST00100 753 305 counterstaining 000000000000000
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P8_ST00101 1075 1161
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P8_ST00102 1172 performed
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P8_ST00103
P8_SP00095 1468
P8_ST00104 1488 249 hematoxylin.
P8_SP00096 1737
P8_ST00105 1769 172 Sections
P8_SP00097 1941
P8_ST00106 1956
P8_TL00010 1259 1853
P8_ST00107 183 observed
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P8_SP00099 539
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P8_ST00110 675 264 magnification
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P8_ST00111 958
P8_SP00102 1061
P8_ST00112 1079 1267 a
P8_SP00103 1100
P8_ST00113 1116 107 Zeiss
P8_SP00104
P8_ST00114 1238 Axiovert 00000001
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P8_ST00115 1417 109 200M
P8_SP00106 1526
P8_ST00116 1546 240 microscope.
P8_SP00107 1786
P8_ST00117 1803 And
P8_SP00108 1881
P8_ST00118 143 images
P8_SP00109 2043
P8_ST00119 2058
P8_TL00011 1364 1930
P8_ST00120 170 obtained
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P8_ST00121 489
P8_SP00111 567
P8_ST00122 583 191 AxioVs40
P8_SP00112 774
P8_ST00123 791 software
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P8_ST00126 1254 Zeiss)
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P8_ST00127 (Carl
P8_SP00117 1486
P8_ST00128 117 Zeiss,
P8_SP00118 1620
P8_ST00129 1638 252 Thornwood).
P8_SP00119 1890
P8_ST00130 1924 253 Enumeration
P8_SP00120 2177
P8_ST00131 37 of
P8_TL00012 1821
P8_ST00132 284 IL17A-positive
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P8_ST00133 88 cells
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P8_ST00134 708
P8_SP00123 787
P8_ST00135 805
P8_SP00124 1007
P8_ST00136 1025 46 on
P8_SP00125 1071
P8_ST00137 60
P8_SP00126 1148
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P8_SP00130 1751
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P8_SP00131 1824
P8_ST00143 1839 whole
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P8_ST00144 1973
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P8_ST00145
P8_SP00133 433 1616
P8_ST00146 451
P8_SP00134 554
P8_ST00147 573 219 Mayachitra
P8_SP00135 792
P8_ST00148 810 119 imago
P8_SP00136 929
P8_ST00149 947 168
P8_SP00137 1115 1607
P8_ST00150 1133 245 (Mayachitra,
P8_SP00138 1378
P8_ST00151 1399 Inc,
P8_SP00139 1465
P8_ST00152
P8_SP00140 1599
P8_ST00153 1618 Barbara,
P8_SP00141
P8_ST00154 1805
P8_SP00142
P8_ST00155 1910 although
P8_TL00014 1680 1536
P8_ST00156 237 lymphocytic
P8_SP00143
P8_ST00157 214 infiltrations
P8_SP00144 769
P8_ST00158 1688 62 are
P8_SP00145 848
P8_ST00159 866 normally
P8_SP00146 1034
P8_ST00160 seen
P8_SP00147 1145
P8_ST00161 1163 80 only
P8_SP00148 1243
P8_ST00162 1261
P8_SP00149 1290
P8_ST00163 1308
P8_SP00150 1368
P8_ST00164 1385 299 submandibular
P8_SP00151 1684
P8_ST00165 1698 141 glands.
P8_TL00015
P8_ST00166 Detection 0.88 050500000
P8_SP00152 508 2029
P8_ST00167 525 45
P8_SP00153 570
P8_ST00168 580 247 antinuclear 0.94 00000000501
P8_SP00154 827
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P8_SP00155 1064
P8_ST00170 124 (ANA)
P8_SP00156 1204 2038
P8_ST00171
P8_SP00157
P8_ST00172 1275 0.83 005
P8_SP00158 1341
P8_ST00173 1355 2005 sera 0510
P8_TL00016 1836
P8_ST00174 ANA
P8_SP00159 393 2134
P8_ST00175
P8_SP00160 439
P8_ST00176
P8_SP00161 517
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P8_SP00162 619
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P8_SP00165 891
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P8_ST00182 1098
P8_SP00167 1201 2143
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P8_SP00168 1344
P8_ST00184 1360
P8_SP00169 1452
P8_ST00185 1470 42 kit
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P8_ST00186 1541 (INOVA
P8_SP00171 1694
P8_ST00187 241 Diagnostics,
P8_SP00172 1954
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P8_SP00173 2040 2141
P8_ST00189 2060 San
P8_TL00017 2207
P8_ST00190 Diego,
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P8_ST00191
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P8_SP00177
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P8_SP00178
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P8_SP00179
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P8_ST00198 1611 instructions.
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P8_SP00183
P8_ST00200
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P8_TL00018 2313
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P8_SP00190 1104
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P8_ST00209 mouse
P8_SP00192 1500
P8_ST00210 1517
P8_SP00193 1602
P8_ST00211 1619 diluted
P8_SP00194
P8_ST00212 1770 1:40,
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P8_ST00213 1884 82 1:80
P8_SP00196 1966
P8_ST00214 1983
P8_SP00197 2054
P8_ST00215 2076 1:160.
P8_TL00019 2418 1782
P8_ST00216 121 Slides
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P8_ST00217 438 2426 96
P8_SP00199
P8_ST00218
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P8_ST00219 762
P8_SP00201 815
P8_ST00220 832
P8_SP00202 844 25
P8_ST00221 hr
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P8_ST00222 921 2419
P8_SP00204 957
P8_ST00223 973 room
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P8_ST00224 244 temperature
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P8_ST00225
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P8_SP00208 1419
P8_ST00227 1437 humidified
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P8_ST00228 1658 chamber.
P8_SP00210
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P8_SP00211 1970
P8_ST00230 101 three
P8_TL00020 2524 1933
P8_ST00231 154 washes
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P8_ST00232 469
P8_SP00213 522
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P8_SP00214 603
P8_ST00234 621 minutes
P8_SP00215 777
P8_ST00235
P8_SP00216 870
P8_ST00236 890 PBS,
P8_SP00217 986 2563
P8_ST00237 1004
P8_SP00218
P8_ST00238 1081
P8_SP00219
P8_ST00239
P8_SP00220
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P8_SP00221 1507
P8_ST00241 1525 covered
P8_SP00222 1682
P8_ST00242
P8_SP00223 1776
P8_ST00243 1793 112 Alexa
P8_SP00224 1905
P8_ST00244 312 488-conjugated
P8_TL00021 2629 1802
P8_ST00245 2630
P8_SP00225 388 2670
P8_ST00246 404 222 anti-mouse
P8_SP00226 2661
P8_ST00247 645 67
P8_SP00227 712
P8_ST00248 731 (HL) 0.91 00400
P8_SP00228
P8_ST00249 846 210 (Invitrogen
P8_SP00229
P8_ST00250 1076
P8_SP00230 1141 2668
P8_ST00251 189 Carlsbad,
P8_SP00231
P8_ST00252 1370 73 CA)
P8_SP00232 1443
P8_ST00253 1461
P8_SP00233 1591
P8_ST00254 1612 1:100
P8_SP00234 1719
P8_ST00255 1736
P8_SP00235 1789
P8_ST00256 47
P8_SP00236 1849
P8_ST00257 1868 min
P8_SP00237 1935
P8_ST00258 1953
P8_SP00238 1989
P8_ST00259 2637 99
P8_TL00022 2734 1864
P8_ST00260 2735 254 temperature.
P8_SP00239 2775
P8_ST00261 585
P8_SP00240 683 2766
P8_ST00262 696
P8_SP00241
P8_ST00263 812 washes,
P8_SP00242 976 2773
P8_ST00264 994 257 fluorescence
P8_SP00243
P8_ST00265 1266 2742
P8_SP00244 1346
P8_ST00266 1362
P8_SP00245
P8_ST00267 1552
P8_SP00246 1595
P8_ST00268 256
P8_SP00247 1867
P8_ST00269 1885 microscopy
P8_SP00248 2112
P8_ST00270 2129
P8_TL00023 2840
P8_ST00271 104
P8_SP00249 405 2872
P8_ST00272 263
P8_SP00250 686 2881
P8_ST00273 706
P8_SP00251 809
P8_ST00274 2848
P8_SP00252
P8_ST00275 864
P8_SP00253 971
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P8_SP00254 1150
P8_ST00277 1165
P8_SP00255 1274
P8_ST00278 229 microscope
P8_SP00256 1523
P8_ST00279 1540
P8_SP00257
P8_ST00280 1629 all 0.90
P8_SP00258 1670
P8_ST00281 1689
P8_SP00259 1832
P8_ST00282 1846
P8_SP00260 1943
P8_ST00283 1960
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P8_ST00284 2147
P8_TL00024 2945 1774
P8_ST00285
P8_SP00262 491 2977
P8_ST00286
P8_SP00263 677
P8_ST00287 692
P8_SP00264 770
P8_ST00288 789 2946 constant
P8_SP00265 959
P8_ST00289 975 2953 exposure
P8_SP00266 1159 2986
P8_ST00290 1176
P8_SP00267 1214
P8_ST00291 1227 59 0.3
P8_SP00268 1286
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P8_SP00269 1471
P8_ST00293
P8_SP00270 1581
P8_ST00294 1598
P8_SP00271 1715 2984
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P23_SP00034 1610 718
P23_ST00038 1632 139 NIDCR
P23_SP00035 1771
P23_ST00039 1789 197 intramural
P23_SP00036 1986
P23_ST00040 2005 172 research
P23_TL00005 302 785 110
P23_ST00041 grant.
P23_TB00002 1248 3047 54 42
P23_TL00006 1254 3053 30
P23_ST00042


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P10_ST00025 1424 peak
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P10_ST00035 966 53 for
P10_SP00032 1019
P10_ST00036 1033 282 approximately
P10_SP00033 1315
P10_ST00037 1330 2
P10_SP00034 1351
P10_ST00038 1367 77 wks
P10_SP00035 1444
P10_ST00039 1462 82 [29].
P10_SP00036 1544 34
P10_ST00040 1578 In
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P10_ST00041 1626 60 the
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P10_ST00042 1703 785 140 current
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P10_ST00047 991 61
P10_SP00043 1052
P10_ST00048 898 presence
P10_SP00044 1253
P10_ST00049 1270
P10_SP00045 1308
P10_ST00050 1323 96 LacZ
P10_SP00046 1419
P10_ST00051 1437 133 protein
P10_SP00047 1570
P10_ST00052 1590
P10_SP00048 1619
P10_ST00053 1636
P10_SP00049 1696
P10_ST00054 1714 142 infused
P10_SP00050 1856
P10_ST00055 1874 151 salivary
P10_SP00051
P10_ST00056 2042 131 glands
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P10_ST00057 demonstrated 000000000000
P10_SP00052 577 1027
P10_ST00058 594 75 that
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P10_SP00054 827 1036
P10_ST00060 844 245
P10_SP00055 1089
P10_ST00061 1107 187 efficiency
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P10_ST00063 1405
P10_SP00058 1687
P10_ST00064 1702 48 26
P10_SP00059 1750
P10_ST00065 1767 1000 22 27
P10_SP00060 1789
P10_ST00066 1805 5%
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P10_ST00068 1934
P10_SP00063 1955
P10_ST00069 1971
P10_SP00064 2048
P10_ST00070 2065 40 post-
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P10_ST00071 infusion
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P10_ST00072 471 113
P10_SP00066 584
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P10_ST00074 828
P10_SP00068 863
P10_ST00075 883
P10_SP00069 927
P10_ST00076 944 1106
P10_SP00070
P10_ST00077 982 3%
P10_SP00071 1042
P10_ST00078 1062 43 by
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P10_ST00079 1122
P10_SP00073 1143
P10_ST00080 1158
P10_SP00074 1235
P10_ST00081 265 post-infusion. 00000000000000
P10_SP00075 1518
P10_ST00082 1549 76 The
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P10_ST00083 1642 88 cells
P10_SP00077 1730
P10_ST00084 1744 within
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P10_ST00085 1875
P10_SP00079 1935
P10_ST00086 1953
P10_TL00008 1206 1882
P10_ST00087
P10_SP00080 433 1247
P10_ST00088 451 150 positive
P10_SP00081 601
P10_ST00089 617
P10_SP00082 670 1238
P10_ST00090 686
P10_SP00083 782
P10_ST00091 799 216 expression
P10_SP00084 1015
P10_ST00092 1031 1214 were
P10_SP00085 1128
P10_ST00093 1146 283 predominantly
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P10_ST00094 1446 117 ductal
P10_SP00087 1563
P10_ST00095 1581 98 39 cells,
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P10_ST00096 1698 as
P10_SP00089 1743
P10_ST00097 1759 192 expected,
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P10_ST00098 71
P10_SP00091
P10_ST00099 2060 124 acinar
P10_TL00009 1311
P10_ST00100
P10_SP00092 390 1343
P10_ST00101 407 99 (data
P10_SP00093 506 1352
P10_ST00102 525 1312 not
P10_SP00094
P10_ST00103 600 154 shown),
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P10_ST00104 774 188 indicating
P10_SP00096 962
P10_ST00105 979
P10_SP00097 1039
P10_ST00106 1055 virus
P10_SP00098 1149
P10_ST00107 1164 1319
P10_SP00099 1243
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P10_ST00109 1433
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P10_ST00112 1823
P10_SP00104 1883
P10_ST00113 1900 116 ducts.
P10_TL00010 1417
P10_ST00114 50 To
P10_SP00105 501 1449
P10_ST00115 518 200 determine
P10_SP00106 718
P10_ST00116 736 if
P10_SP00107 757
P10_ST00117 769 246
P10_SP00108
P10_ST00118 37
P10_SP00109
P10_ST00119 1084
P10_SP00110 1458
P10_ST00120 1252
P10_SP00111 1383
P10_ST00121 1398 78
P10_SP00112 1476
P10_ST00122 1496 129 IL-17A
P10_SP00113
P10_ST00123 108 alters
P10_SP00114
P10_ST00124 1766
P10_SP00115 1826
P10_ST00125 1425 122 serum
P10_SP00116 1965
P10_ST00126 1983
P10_TL00011 1522 1910
P10_ST00127 profiles,
P10_SP00117 456
P10_ST00128 475 1530
P10_SP00118 597 1554
P10_ST00129 616 250 preparations
P10_SP00119 866
P10_ST00130 881
P10_SP00120
P10_ST00131 assessed
P10_SP00121 1183
P10_ST00132 1200 54
P10_SP00122 1254
P10_ST00133 1266 175 temporal
P10_SP00123 1441
P10_ST00134 1459 169 changes
P10_SP00124 1628
P10_ST00135 1646
P10_SP00125 1675
P10_ST00136 1694 339 pro-inflammatory 0000000000000000
P10_SP00126 2033
P10_ST00137 2050 163
P10_TL00012
P10_ST00138 levels.
P10_SP00127 425 1660
P10_ST00139 445 92 Sera
P10_SP00128 537
P10_ST00140 554
P10_SP00129 592
P10_ST00141 604 treated
P10_SP00130 742
P10_ST00142 762 mice
P10_SP00131 853
P10_ST00143 868
P10_SP00132 965
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P10_ST00145 1176 1629
P10_SP00134 1211
P10_ST00146 1227 93 days
P10_SP00135 1320 1669
P10_ST00147 1336
P10_SP00136 1357
P10_ST00148 1374
P10_SP00137 1445
P10_ST00149 1467 42
P10_SP00138 1509
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P10_ST00151 1835
P10_SP00140
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P10_TL00013 1733
P10_ST00154 efficacy
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P10_ST00155 470
P10_SP00143 508 1765
P10_ST00156 520
P10_SP00144
P10_ST00157
P10_SP00145 729
P10_ST00158 745 217 expressing
P10_SP00146
P10_ST00159 viral
P10_SP00147 1059
P10_ST00160 1076 1734 144
P10_SP00148 1220
P10_ST00161 1236
P10_SP00149 1271
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P10_ST00163 1413
P10_SP00151 1576
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P10_SP00153
P10_ST00166 127 shown
P10_SP00154 2034
P10_ST00167 2053
P10_SP00155 2083
P10_ST00168 134 Figure
P10_TL00014 1828 1830
P10_ST00169 1838 1,
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P10_ST00170 353 195 C57BL6J 0.93 00000400
P10_SP00157 548
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P10_SP00160
P10_ST00174
P10_SP00161 986
P10_ST00175 1001 Ad5-IL17A
P10_SP00162 1216
P10_ST00176 1231
P10_SP00163 1356
P10_ST00177 1370
P10_SP00164
P10_ST00178 1423 10'^ 0.59 00610
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P10_ST00179 1499
P10_SP00166 1579
P10_ST00180 1598 166 particles 000100000
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P10_ST00181 1781 1846 64 per
P10_SP00168 1845
P10_ST00182
P10_SP00169 2011
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P10_SP00182 1915
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P10_SP00183 2046
P10_ST00198 2063 or
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P10_ST00203 821
P10_SP00188
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P10_SP00205
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P10_SP00211
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P10_SP00216
P10_ST00234 1335
P10_SP00217 1396
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P10_SP00218
P10_ST00236 1716
P10_SP00219 1880 2301
P10_ST00237 1899 72
P10_SP00220
P10_ST00238 1988 174
P10_TL00019 2365
P10_ST00239 cannulation.
P10_SP00221 542 2397
P10_ST00240 Thus,
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P10_ST00241 701
P10_SP00223 761
P10_ST00242 777 2366
P10_SP00224
P10_ST00243 939 gain
P10_SP00225 1020 2406
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P10_ST00245 1195 into
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P10_ST00246 1279
P10_SP00228 1340
P10_ST00247
P10_SP00229 1488
P10_ST00248 1504
P10_SP00230 1575
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P10_ST00250 secrete
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P10_SP00233 2115
P10_ST00252
P10_TL00020 2471 773
P10_ST00253 quantities
P10_SP00234 494 2512
P10_ST00254 510
P10_SP00235 2503
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P10_ST00256 systemic
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P10_TL00021 2682
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P10_ST00259 529 191 numbers 0.90 0000510
P10_SP00239
P10_ST00260
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P10_ST00261 790 378 IL-17A-producing 0000000010000000
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P10_ST00271 1959 L1 0.89 02
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P10_ST00273
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P31_ST00039 1312 139 treated
P31_SP00036 1451
P31_ST00040 1469 35
P31_SP00037 1504
P31_ST00041 1520 7
P31_SP00038
P31_ST00042 1556
P31_SP00039 1633
P31_ST00043 1650
P31_SP00040 1687
P31_ST00044 1701 740 72 age
P31_SP00041 1773
P31_ST00045 1791 109 (early
P31_SP00042 1900
P31_ST00046 1916 205 treatment)
P31_SP00043 2121
P31_ST00047 2139 39 or
P31_SP00044 2178
P31_ST00048 2192
P31_TL00005 837 1855
P31_ST00049 12 1
P31_SP00045 317 869
P31_ST00050 330
P31_SP00046 22
P31_ST00051
P31_SP00047
P31_ST00052 458 838 225
P31_SP00048 683 878
P31_ST00053 698
P31_SP00049 874
P31_ST00054 890
P31_SP00050 928
P31_ST00055 942 92
P31_SP00051 1034
P31_ST00056 1050 138
P31_SP00052 1188
P31_ST00057 1206
P31_SP00053 1242
P31_ST00058 1260
P31_SP00054 1304
P31_ST00059 1319
P31_SP00055 1396
P31_ST00060 1413
P31_SP00056 1450
P31_ST00061 845
P31_SP00057 1536
P31_ST00062 1554 84 (late
P31_SP00058 1638
P31_ST00063 1654 216 treatment).
P31_SP00059 1870 34
P31_ST00064 1904 134 Panels
P31_SP00060 2038
P31_ST00065 2055 105 show
P31_TL00006 1861
P31_ST00066 285 representative 00000000000000
P31_SP00061 588 983
P31_ST00067 607 88 H&E
P31_SP00062 695 974
P31_ST00068 712 staining
P31_SP00063
P31_ST00069 883
P31_SP00064 920
P31_ST00070 934 151
P31_SP00065 1085
P31_ST00071 1102 107
P31_SP00066 1209
P31_ST00072 1226 116 tissue
P31_SP00067 1342
P31_ST00073 1358 from
P31_SP00068 1446
P31_ST00074 1465
P31_SP00069
P31_ST00075 1574 177 receiving
P31_SP00070 1751
P31_ST00076 1769 96
P31_SP00071 1865
P31_ST00077 1880 943 192 treatment
P31_SP00072 2072
P31_ST00078 2086 78 with
P31_TL00007 300 1048 1940
P31_ST00079 197 Ad5-LacZ
P31_SP00073 497 1080
P31_ST00080 514 128 (n 10)
P31_SP00074 642 1089
P31_ST00081 661 (A),
P31_SP00075 730
P31_ST00082 749 1056
P31_SP00076 789
P31_ST00083 801 215 Ad5-IL17A
P31_SP00077 1016
P31_ST00084 1033 11)
P31_SP00078 1161
P31_ST00085 1179 (B);
P31_SP00079 1248
P31_ST00086 1266 223 fluorescent
P31_SP00080 1489
P31_ST00087
P31_SP00081 1657
P31_ST00088 1675
P31_SP00082 1746
P31_ST00089 1764 250 enumeration
P31_SP00083 2014
P31_ST00090 2032
P31_SP00084 2069
P31_ST00091 2085 B
P31_SP00085 2109
P31_ST00092 2126
P31_SP00086 2197
P31_ST00093 2214 T
P31_TL00008 1923
P31_ST00094 cells
P31_SP00087 390 1185
P31_ST00095 407 30 in
P31_SP00088 437
P31_ST00096 453
P31_SP00089 668
P31_ST00097
P31_SP00090 821
P31_ST00098 841
P31_SP00091 932
P31_ST00099 950 43 (C
P31_SP00092 993 1194
P31_ST00100 1010 &
P31_SP00093
P31_ST00101 1057 D)
P31_SP00094 1099
P31_ST00102 1117
P31_SP00095
P31_ST00103 1207 435 immunohistochemical 0000000000000000000
P31_SP00096 1642
P31_ST00104 152
P31_SP00097 1812
P31_ST00105 1830
P31_SP00098 1901
P31_ST00106 1920 249
P31_SP00099 2169
P31_ST00107 2187
P31_TL00009 1259 1874
P31_ST00108 299 IL-17A-positive 000000000000000
P31_SP00100 603 1300
P31_ST00109 620
P31_SP00101 708 1291
P31_ST00110 726 29
P31_SP00102 755
P31_ST00111 771
P31_SP00103 986
P31_ST00112 1002
P31_SP00104 1140
P31_ST00113 1159
P31_SP00105 1250
P31_ST00114 1269 (E
P31_SP00106 1309
P31_ST00115 1326
P31_SP00107 1356
P31_ST00116 1373 48 F);
P31_SP00108 1421
P31_ST00117 1443 87
P31_SP00109 1530
P31_ST00118 1548
P31_SP00110 1700
P31_ST00119 1718
P31_SP00111 1756
P31_ST00120
P31_SP00112 1921
P31_ST00121 1937
P31_SP00113 2044
P31_ST00122 2061 117
P31_TL00010 1364 1781
P31_ST00123
P31_SP00114 389
P31_ST00124
P31_SP00115 499
P31_ST00125 517
P31_SP00116 694 1405
P31_ST00126 713
P31_SP00117 782
P31_ST00127 798 1365
P31_SP00118 990
P31_ST00128 1003
P31_SP00119 1081
P31_ST00129 1097
P31_SP00120 1294
P31_ST00130 127
P31_SP00121 1439
P31_ST00131 1458 (G),
P31_SP00122 1529
P31_ST00132 1549 1372
P31_SP00123 1588
P31_ST00133 1600 184 Ad5-IL17
P31_SP00124 1784
P31_ST00134 1802 102 8)
P31_SP00125
P31_ST00135 (H);
P31_SP00126 1992
P31_ST00136 2011
P31_TL00011 1860
P31_ST00137
P31_SP00127 524 1501 28
P31_ST00138 552
P31_SP00128 704 1510
P31_ST00139 722
P31_SP00129 793
P31_ST00140 812
P31_SP00130 1061
P31_ST00141 1079
P31_SP00131
P31_ST00142 1132
P31_SP00132 1156
P31_ST00143 1173
P31_SP00133 1244
P31_ST00144 1262
P31_SP00134 1288
P31_ST00145 1303
P31_SP00135 1391
P31_ST00146 1409
P31_SP00136 1438
P31_ST00147 1454
P31_SP00137 1669
P31_ST00148 1684
P31_SP00138 1823
P31_ST00149 1842
P31_SP00139 1933
P31_ST00150 (I
P31_SP00140 1973
P31_ST00151 1991
P31_SP00141 2021
P31_ST00152 2036 J)
P31_SP00142
P31_ST00153 2090
P31_TL00012 1575 1869
P31_ST00154
P31_SP00143 738 1607
P31_ST00155 756
P31_SP00144 908 1616
P31_ST00156 926
P31_SP00145 997
P31_ST00157 1015
P31_SP00146 1265
P31_ST00158 1283
P31_SP00147 1320
P31_ST00159 1336
P31_SP00148 1635
P31_ST00160 1652
P31_SP00149 1740
P31_ST00161 1758
P31_SP00150 1787
P31_ST00162 1803
P31_SP00151 2018
P31_ST00163 2034
P31_TL00013 1680 1452
P31_ST00164
P31_SP00152 394 1712
P31_ST00165 413 (K
P31_SP00153 1721
P31_ST00166 473
P31_SP00154 503
P31_ST00167 49 L).
P31_SP00155 568
P31_ST00168 589 Black
P31_SP00156 696
P31_ST00169 1688 arrows
P31_SP00157 846
P31_ST00170 863 indicate
P31_SP00158
P31_ST00171
P31_SP00159
P31_ST00172 1337 237 lymphocytic
P31_SP00160
P31_ST00173 1589 166 infiltrate.
P31_TL00014 1891 1699
P31_ST00174
P31_SP00161 1932
P31_ST00175 454 4.
P31_SP00162
P31_ST00176 279 Identification
P31_SP00163
P31_ST00177 816
P31_SP00164 858
P31_ST00178 870 67 the
P31_SP00165 937
P31_ST00179 953 245 antinuclear
P31_SP00166 1198
P31_ST00180 1210 226 antibodies
P31_SP00167 1436
P31_ST00181
P31_SP00168 1488
P31_ST00182 1506 1899 90 sera
P31_SP00169 1596
P31_ST00183 1614
P31_SP00170 1656
P31_ST00184 1670 203 C57BL6J 00000800
P31_SP00171 1873
P31_ST00185 1892 mice.
P31_TL00015 1997
P31_ST00186 Representative
P31_SP00172 606
P31_ST00187 624 1998 161 patterns
P31_SP00173 785
P31_ST00188
P31_SP00174 839 2029
P31_ST00189 852 144 cellular
P31_SP00175 996
P31_ST00190
P31_SP00176 1163
P31_ST00191 1181
P31_SP00177 1218
P31_ST00192 1234 122 HEp-2
P31_SP00178
P31_ST00193 1375
P31_SP00179 1462
P31_ST00194 1480 by
P31_SP00180 1524
P31_ST00195 1540 2005 85
P31_SP00181 1625
P31_ST00196 130 diluted
P31_SP00182 1772
P31_ST00197 1790
P31_SP00183 1825
P31_ST00198 1844 1:40
P31_SP00184 1925
P31_ST00199 1944 prepared
P31_SP00185
P31_ST00200 2138
P31_TL00016 2102 1922
P31_ST00201 2110
P31_SP00186 387 2134
P31_ST00202 403 108 taken
P31_SP00187 511
P31_ST00203
P31_SP00188 615
P31_ST00204 633 174 C57BL6 0.92 0000040
P31_SP00189 807
P31_ST00205 825
P31_SP00190 917
P31_ST00206 219 cannulated
P31_SP00191
P31_ST00207 1169
P31_SP00192 1247
P31_ST00208 1263
P31_SP00193 1460
P31_ST00209 1476
P31_SP00194 1516
P31_ST00210 1528
P31_SP00195 1743
P31_ST00211 2103 145 vectors
P31_SP00196 1903
P31_ST00212
P31_SP00197 1955
P31_ST00213 1971
P31_SP00198
P31_ST00214 2007
P31_SP00199 2084
P31_ST00215 2101
P31_SP00200
P31_ST00216 2152
P31_TL00017 2207 1879
P31_ST00217
P31_SP00201 378 2239
P31_ST00218 397 218 pre-treated
P31_SP00202 2248
P31_ST00219
P31_SP00203
P31_ST00220 744 195 (baseline)
P31_SP00204 939
P31_ST00221 957 2208
P31_SP00205 992
P31_ST00222 1007 6
P31_SP00206 1029
P31_ST00223 1044
P31_SP00207 1121
P31_ST00224 1138
P31_SP00208 1175
P31_ST00225 1189 2215
P31_SP00209
P31_ST00226 1279 4)
P31_SP00210 1381
P31_ST00227 1400 (A-C),
P31_SP00211 1517
P31_ST00228
P31_SP00212
P31_ST00229
P31_SP00213
P31_ST00230 1862 at16
P31_SP00214 1947
P31_ST00231
P31_SP00215 2039
P31_ST00232 2056
P31_SP00216 2093
P31_ST00233 2107
P31_TL00018 2313
P31_ST00234
P31_SP00217 2345
P31_ST00235
P31_SP00218 591
P31_ST00236 2321
P31_SP00219 647
P31_ST00237 659
P31_SP00220
P31_ST00238 891
P31_SP00221 962
P31_ST00239 981 217
P31_SP00222 2354
P31_ST00240
P31_SP00223
P31_ST00241 1327
P31_SP00224 1522
P31_ST00242 2314
P31_SP00225 1576
P31_ST00243 1594
P31_SP00226
P31_ST00244 1653
P31_SP00227 1730
P31_ST00245 1747
P31_SP00228
P31_ST00246 1798
P31_SP00229
P31_ST00247 1888
P31_SP00230 1990
P31_ST00248 2009 100 (D-F)
P31_SP00231
P31_ST00249 2125
P31_TL00019 2418 1886
P31_ST00250 168 negative
P31_SP00232 471 2459
P31_ST00251 488 132 control
P31_SP00233 2450
P31_ST00252 639
P31_SP00234 742
P31_ST00253 761 207 secondary
P31_SP00235 968
P31_ST00254 985 antibody
P31_SP00236 1154
P31_ST00255 1171 only
P31_SP00237 1251
P31_ST00256 61 (G)
P31_SP00238 1330
P31_ST00257 1347
P31_SP00239 1418
P31_ST00258 1437 150 positive
P31_SP00240 1587
P31_ST00259 1604
P31_SP00241 1736
P31_ST00260 1752
P31_SP00242
P31_ST00261 1849 172 standard
P31_SP00243
P31_ST00262 2041 148 nuclear
P31_TL00020 2524
P31_ST00263 175 speckled
P31_SP00244 477 2565
P31_ST00264 496 2532 serum
P31_SP00245 618 2556
P31_ST00265 637 68 (H).
P31_SP00246 705
P31_ST00266
P31_SP00247 1042
P31_ST00267 1060 2525
P31_SP00248 1221
P31_ST00268 1235 97 were
P31_SP00249 1332
P31_ST00269 1349 determined
P31_SP00250 1573
P31_ST00270 1590
P31_SP00251 1668
P31_ST00271 1686 73 n 4
P31_SP00252 1759
P31_ST00272 1775 53 for
P31_SP00253 1828
P31_ST00273 1841 two
P31_SP00254 1909
P31_ST00274 1927 189 baselines
P31_SP00255 2116
P31_ST00275 2132
P31_TL00021 2629 1878
P31_ST00276
P31_SP00256 375 2661
P31_ST00277 391 54
P31_SP00257 445
P31_ST00278 459 94 each
P31_SP00258 553
P31_ST00279 570 83 time
P31_SP00259 653
P31_ST00280 671 point
P31_SP00260 767 2670
P31_ST00281 783 198 presented
P31_SP00261
P31_ST00282 1000
P31_SP00262
P31_ST00283 1046 60
P31_SP00263 1106
P31_ST00284 1123 121 figure.
P31_SP00264
P31_ST00285 1278 Fixed
P31_SP00265 1383
P31_ST00286 1403 123
P31_SP00266 1526
P31_ST00287 1544 substrate
P31_SP00267 1728
P31_ST00288 1745 114 slides
P31_SP00268 1859
P31_ST00289 2637
P31_SP00269 1970
P31_ST00290 1988 incubated
P31_TL00022 2734 1858
P31_ST00291
P31_SP00270 2766
P31_ST00292 185 individual
P31_SP00271 582
P31_ST00293 601 2742 mouse
P31_SP00272
P31_ST00294 750
P31_SP00273 835
P31_ST00295
P31_SP00274 982
P31_ST00296 1:40,
P31_SP00275 1095 2773 23
P31_ST00297 1118 82 1:80
P31_SP00276 1200
P31_ST00298 1217
P31_SP00277
P31_ST00299 1:160
P31_SP00278 1416
P31_ST00300 1433 followed
P31_SP00279
P31_ST00301
P31_SP00280 1659 2775
P31_ST00302 1676 260 development
P31_SP00281 1936
P31_ST00303 1949
P31_SP00282
P31_ST00304 111 FITC- 0.98
P31_TL00023 2840 1726
P31_ST00305 conjugated
P31_SP00283 521 2881
P31_ST00306 539 2841 86 goat
P31_SP00284 625
P31_ST00307 641 222 anti-mouse
P31_SP00285 2872
P31_ST00308 882 IgG.
P31_SP00286
P31_ST00309 235 Fluorescent
P31_SP00287
P31_ST00310 1233
P31_SP00288 1394
P31_ST00311 1408 2848
P31_SP00289 1505
P31_ST00312 171 detected
P31_SP00290 1693
P31_ST00313
P31_SP00291
P31_ST00314 1771 257 fluorescence
P31_TL00024 2945 988
P31_ST00315 227 microscopy
P31_SP00292 530 2986
P31_ST00316 547 2946
P31_SP00293 2977
P31_ST00317 596 400X
P31_SP00294 701
P31_ST00318 718 275 magnification.
P31_SP00295 261
P31_ST00319 1254 3053


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P36_SP00003 565 59 17
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P36_SP00004 772 10
P36_ST00005 782 14 28 "J 0.17 78
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P36_TB00002 114 382 196
P36_TL00002 386 193 24
P36_ST00006 387 23 C. 0.96 00
P36_SP00005 138 410
P36_ST00007 148 159 Ad5:IL-17A 0.86 3025000002
P36_TB00003 425 373 572 354
P36_TL00003 588 376 64
P36_ST00008 58 D.A 1.00 000
P36_SP00006 646 399 -34
P36_ST00009 612 418 40 22 100i 0.24 7778
P36_TL00004 586 453 61 95
P36_ST00010 62 |.. 0.42 8760
P36_SP00007 647 515 -57
P36_ST00011 590 529 19 g 0.13
P36_SP00008 600 548
P36_ST00012 622 528 18 CD 88 SUBS_TYPE HypPart1 SUBS_CONTENT CD'S
P36_TL00005 554 47
P36_ST00013 'S 0.20 HypPart2
P36_SP00009 599 -9
P36_ST00014 581 20 S)
P36_SP00010 603 601
P36_ST00015 25 15 40- 0.25 776
P36_TL00006 635
P36_ST00016 9 S
P36_SP00011 654
P36_ST00017 623 638 20- 0.23 777
P36_TL00007 676 11
P36_ST00018 a. 0.21 87
P36_TL00008 652 375 123
P36_ST00019 d5-IL17A 0.75 80203104
P36_TL00009 426 628 53
P36_ST00020 B220 0.68 4007
P36_TL00010 657 51
P36_ST00021 CDS: 0.71 1180
P36_TL00011 496 41
P36_ST00022 Red 0.60 326
P36_TL00012 492 656
P36_ST00023 Green 0.73 50250
P36_SP00012 558 674 -62
P36_ST00024 684 48 16 Blue 0.22 8886
P36_TL00013 723 713
P36_ST00025 CD3+ 0.34 6666
P36_TL00014 911
P36_ST00026 B22Q+ 0.37 27876
P36_TB00004 1042 370 508 110
P36_TB00005 1054 210
P36_TB00006 1552 200
P36_TL00015 1555 392 181
P36_ST00027 394 21 F.
P36_SP00013 1576 416
P36_ST00028 1587 149 Ad5-IL17A 0.87 330000003
P36_TB00007 1356 686 174 34
P36_TL00016 1360 687 154 29
P36_ST00029 688 90 r-Kia 0.15 878888
P36_SP00014 1450 716
P36_ST00030 1467 ^i^ 0.04 10810
P36_TB00008 1554 670 455 60
P36_TL00017 1557 439
P36_ST00031 0.82 1
P36_SP00015 1567 690 75
P36_ST00032 1642 675 4 0.61 3
P36_SP00016 1652
P36_ST00033 1727 0.46
P36_SP00017 1736 71
P36_ST00034 1807 0.31
P36_SP00018 1827
P36_ST00035 1891 0.29 68
P36_SP00019 1911
P36_ST00036 1976 0.40
P36_TL00018 1559 705 430
P36_ST00037 Percentage 0.69 4400507701
P36_SP00020 1673 725 7
P36_ST00038 1680 of 0.91
P36_SP00021 1700 721 6
P36_ST00039 1706 cells 0.80 04005
P36_SP00022 1750
P36_ST00040 1758 710 33 per 0.67 450
P36_SP00023 1791
P36_ST00041 1798 112 histological 004760700470
P36_SP00024 1910
P36_ST00042 1918 706 section 4406061
P36_TB00009 96 758 128
P36_TL00019 764
P36_ST00043 765 G. 0.77
P36_SP00025 141 788
P36_ST00044 151 73 Ad5-I 0.79 03240
P36_CB2_SUB 760 1470 698
P36_TB00010 1584 1126 168
P36_TL00020 1588 1131
P36_ST00045 0.90 300020301
P36_TB00011 1272 1234 278 76
P36_TL00021 1287 1264 255
P36_ST00046 67 Ts"*^ 887610
P36_SP00026 1354 1293 2
P36_ST00047 1275 Ji 0.19 887
P36_SP00027 1388
P36_ST00048 1396 31 f-- 0.26
P36_SP00028 1427 1291
P36_ST00049 1441 1267 26 f'
P36_SP00029 1469
P36_ST00050 1501 1273 *'~ 0.56 606
P36_TB00012 1288 504 130
P36_TB00013 1460 150
P36_TL00022 1463 118
P36_ST00051 Figure 0.92 000005
P36_SP00030 143 1496
P36_ST00052 155 1464
P36_TB00014 1094 1436 70 30
P36_TL00023 1096 1440 63
P36_ST00053 Ji.S4 887858
P36_TB00015 1156 1386
P36_TB00016 1542 1410
P36_TL00024 1620 1413 363
P36_ST00054 1417 ) 0.18
P36_SP00031 1625 1428 45
P36_ST00055 1670 0.78 03
P36_SP00032 1689
P36_ST00056 1729 0.63 07
P36_SP00033 1748
P36_ST00057 1786
P36_SP00034 1806 39
P36_ST00058 1845
P36_SP00035 1865
P36_ST00059 1904 57
P36_SP00036 1924
P36_ST00060 1963 35 0.51 54
P36_TL00025 1558 1443 417
P36_ST00061 1501603804
P36_SP00037 1668 1462
P36_ST00062 1676 50
P36_SP00038 1695 1458
P36_ST00063 05050
P36_SP00039 1744
P36_ST00064 1752 1447 140
P36_SP00040 1783
P36_ST00065 1790 109 0.81 044040100080
P36_SP00041 1899
P36_ST00066 1906 69 0.85 4002030


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P15_ST00077 1633 81 [34].
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P15_ST00295 148 nuclear
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P15_SP00282 998
P15_ST00306
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P15_ST00309
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P15_ST00310 1511 2893
P15_SP00287
P15_ST00311 1676
P15_SP00288
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P15_SP00290
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P25_ST00248 receptor
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P25_ST00251
P25_SP00231
P25_ST00252 300
P25_SP00232 2013
P25_ST00253 2032 2426 180 33 program
P25_TL00022 2524 1429
P25_ST00254
P25_SP00233 494 2556
P25_ST00255 509 357 proinflammatory
P25_SP00234 866 2565
P25_ST00256 883 IL-1
P25_SP00235 954
P25_ST00257 46 7+
P25_SP00236
P25_ST00258 1029
P25_SP00237 1055
P25_ST00259
P25_SP00238
P25_ST00260
P25_SP00239 1328
P25_ST00261 1349 Ce2006, 0.78 156600000
P25_SP00240 1547 2563
P25_ST00262 313 126:1121-1133.
P25_TL00023 2629
P25_ST00263 16.
P25_SP00241 2661
P25_ST00264
P25_SP00242 609
P25_ST00265 623 CT,
P25_SP00243 2668
P25_ST00266
P25_SP00244 839
P25_ST00267 859
P25_SP00245 929
P25_ST00268 950
P25_SP00246 2670
P25_ST00269 1129
P25_SP00247 1197
P25_ST00270 1218
P25_SP00248
P25_ST00271 1445 LE:
P25_SP00249 1505
P25_ST00272 1525 IL-17
P25_SP00250 1627
P25_ST00273 1642 131 family
P25_SP00251 1773
P25_ST00274 1789
P25_SP00252
P25_ST00275
P25_SP00253 2089
P25_ST00276
P25_TL00024 2734
P25_ST00277 224 expanding
P25_SP00254 675 2775
P25_ST00278 694 diversity
P25_SP00255 879
P25_ST00279 895
P25_SP00256 2766
P25_ST00280
P25_SP00257 1119
P25_ST00281 1132
P25_SP00258 1158
P25_ST00282 1173 cell
P25_SP00259 1244
P25_ST00283 1263 188
P25_SP00260 1451
P25_ST00284 106 Annu
P25_SP00261
P25_ST00285 1591 Rev
P25_SP00262 1672
P25_ST00286 1686
P25_SP00263 1861
P25_ST00287 1873 2007, 0.55 58800
P25_SP00264 2773
P25_ST00288 2001 25:821-852.
P25_TB00002 3047
P25_TL00025 3053
P25_ST00289


xml version 1.0 encoding UTF-8
alto xmlns:xsi http:www.w3.org2001XMLSchema-instance xsi:noNamespaceSchemaLocation http:schema.ccs-gmbh.commetaealto-1-2.xsd xmlns:xlink http:www.w3.orgTRxlink
Description
MeasurementUnit pixel
sourceImageInformation
fileName Z:\Scan\Mariner\IR SS\OCR\IR00000341_00001\NguyenCQ_Manuscript_IRUF_Page_11.tif
OCRProcessing ID OCRPROCESSING_1
preProcessingStep
processingSoftware
softwareCreator Kirtas Technologies, Inc.
softwareName BookScan Editor
softwareVersion 3.6
ocrProcessingStep
Kirtas Technologies, Inc.
OCR Manager
3.0.0.0
Layout
Page P11 PHYSICAL_IMG_NR 11 HEIGHT 3300 WIDTH 2550
TopMargin P11_TM00001 HPOS 0 VPOS 304
LeftMargin P11_LM00001 295 2785
RightMargin P11_RM00001 2250 300
BottomMargin P11_BM00001 3089 211
PrintSpace P11_PS00001 1955
TextBlock P11_TB00001
TextLine P11_TL00001 450 310 1689 41
String P11_ST00001 52 32 CONTENT As WC 1.00 CC 00
SP P11_SP00001 502 342 17
P11_ST00002 519 208 mentioned 000000000
P11_SP00002 727 19
P11_ST00003 746 previously, 00000000000
P11_SP00003 957 351 20
P11_ST00004 977 151 salivary 00000000
P11_SP00004 1128
P11_ST00005 1145 131 glands 000000
P11_SP00005 1276 15
P11_ST00006 1291 318 97 24 were 0000
P11_SP00006 1388
P11_ST00007 1405 219 cannulated 0000000000
P11_SP00007 1624 16
P11_ST00008 1640 78 with
P11_SP00008 1718
P11_ST00009 1734 215 Ad5-IL17A
P11_SP00009 1949
P11_ST00010 1965 311 124 31 vector
P11_SP00010 2089 14
P11_ST00011 2103 36 at
P11_TL00002 302 415 1873
P11_ST00012 113 either
P11_SP00011 447
P11_ST00013 429 21 7
P11_SP00012
P11_ST00014 466 77 wks 000
P11_SP00013 543
P11_ST00015 559 423 40 or
P11_SP00014 599
P11_ST00016 616 43
P11_SP00015 659
P11_ST00017 674
P11_SP00016 751
P11_ST00018 768 38 of
P11_SP00017 806 13
P11_ST00019 819 82 33 age.
P11_SP00018 901 456
P11_ST00020 933 75 The
P11_SP00019 1008
P11_ST00021 1024 84 time
P11_SP00020 1108 18
P11_ST00022 1126 117 points
P11_SP00021 1243
P11_ST00023 1260 142 chosen
P11_SP00022 1402
P11_ST00024 1420 62 are
P11_SP00023 1482
P11_ST00025 1500 119 based 00000
P11_SP00024 1619
P11_ST00026 1637 45 on
P11_SP00025 1682
P11_ST00027 1701 189 extensive
P11_SP00026 1890
P11_ST00028 1907 141 studies 0000000
P11_SP00027 2048
P11_ST00029 2065
P11_SP00028 12
P11_ST00030 2115 60 the
P11_TL00003 521 1942
P11_ST00031 260 development
P11_SP00029 562
P11_ST00032 577 71 and
P11_SP00030 648 553
P11_ST00033 666 522 110 onset
P11_SP00031 776
P11_ST00034 791
P11_SP00032 829
P11_ST00035 842 154 disease
P11_SP00033 996
P11_ST00036 1014 29 in
P11_SP00034 1043
P11_ST00037 1061 529 65 our
P11_SP00035
P11_ST00038 1140 515 C57BL6.NOD-Aec'Aec2 0.63 00000400000088476888475
P11_SP00036 1655
P11_ST00039 1671 132 mouse
P11_SP00037 1803
P11_ST00040 1822 118 model
P11_SP00038 1940
P11_ST00041 1958
P11_SP00039 1996
P11_ST00042 2009 57 SS 0.98
P11_SP00040 2066
P11_ST00043 2084 [1-3,
P11_SP00041 2168
P11_ST00044 2187 39 30,
P11_TL00004 626 1923
P11_ST00045 70 31].
P11_SP00042 372 667
P11_ST00046 403
P11_SP00043 478 658
P11_ST00047 495 627 68 two
P11_SP00044 563
P11_ST00048 579 83
P11_SP00045 662
P11_ST00049 680
P11_SP00046 798
P11_ST00050 814 165 selected
P11_SP00047 979
P11_ST00051 999 190 represent
P11_SP00048 1189
P11_ST00052 1203
P11_SP00049 1263
P11_ST00053 1282 innate
P11_SP00050 1401
P11_ST00054 1418
P11_SP00051 1489
P11_ST00055 1508 169 adaptive
P11_SP00052 1677
P11_ST00056 1695 157 immune
P11_SP00053 1852
P11_ST00057 1871 634 183 response
P11_SP00054 2054
P11_ST00058 2072 153 phases,
P11_TL00005 303 732 1786
P11_ST00059 247 respectively, 0000000000000
P11_SP00055 550 773
P11_ST00060 571
P11_SP00056 600 764
P11_ST00061 617
P11_SP00057 677
P11_ST00062 694
P11_SP00058 848
P11_ST00063 866 130 model,
P11_SP00059 771
P11_ST00064 thus
P11_SP00060 1098
P11_ST00065 1114 they
P11_SP00061 1198
P11_ST00066 1212 740
P11_SP00062 1309
P11_ST00067 1326 143
P11_SP00063 1469
P11_ST00068 1486 733 34 to
P11_SP00064 1520
P11_ST00069 1539 116 mimic
P11_SP00065
P11_ST00070 1669 109 these
P11_SP00066 1778
P11_ST00071 1795 170 changes
P11_SP00067
P11_ST00072 1982
P11_SP00068 2011
P11_ST00073 2028 61
P11_TL00006 837 1768
P11_ST00074 159 parental
P11_SP00069 462 878
P11_ST00075 480 174 C57BL6 0.92 0000040
P11_SP00070 654 869
P11_ST00076 672 845 mouse.
P11_SP00071 815
P11_ST00077 212 Microarray
P11_SP00072 1060
P11_ST00078 1077 177 analyses
P11_SP00073 1254
P11_ST00079 1270 193 examined
P11_SP00074 1463
P11_ST00080 1481
P11_SP00075 1541
P11_ST00081 1557 temporal
P11_SP00076 1731
P11_ST00082 1749 206 differential 000000000000
P11_SP00077
P11_ST00083 1973 98 gene
P11_TL00007 942 1760
P11_ST00084 216 expression
P11_SP00078 518 983
P11_ST00085 536
P11_SP00079 574 974
P11_ST00086 587 152
P11_SP00080 739
P11_ST00087 755
P11_SP00081 826
P11_ST00088 846 lacrimal
P11_SP00082 997
P11_ST00089 1015
P11_SP00083 1147
P11_ST00090 1163
P11_SP00084 1201
P11_ST00091 1214
P11_SP00085
P11_ST00092 1406 91 mice
P11_SP00086 1497
P11_ST00093 1516 revealed
P11_SP00087 1685
P11_ST00094 1703 148 gradual
P11_SP00088 1851
P11_ST00095 1869 146 change
P11_SP00089 2015
P11_ST00096 2033
P11_TL00008 1048 1909
P11_ST00097 371 pathophysiological 000000000000000000
P11_SP00090 1089
P11_ST00098 693 134 related
P11_SP00091 827 1080
P11_ST00099 1056 121 genes
P11_SP00092 966
P11_ST00100 981 88 from
P11_SP00093 1069
P11_ST00101 1090 16-20
P11_SP00094 1200
P11_ST00102 1215
P11_SP00095 1292
P11_ST00103 1308
P11_SP00096 1346
P11_ST00104 1359 age,
P11_SP00097 1442
P11_ST00105 1461 286 concomitantly, 00000000000000
P11_SP00098 1747
P11_ST00106 188 leukocyte
P11_SP00099 1956
P11_ST00107 1974 infiltration
P11_SP00100 2164
P11_ST00108 2183
P11_TL00009 301 1153 1885
P11_ST00109
P11_SP00101 361 1185
P11_ST00110 379 168 exocrine
P11_SP00102 547
P11_ST00111 565
P11_SP00103 696 1194
P11_ST00112 713 is
P11_SP00104 742
P11_ST00113 758 often
P11_SP00105 855
P11_ST00114 873 observed
P11_SP00106
P11_ST00115 1074 1154
P11_SP00107 1110
P11_ST00116 1124
P11_SP00108 1233
P11_ST00117 1250 1161 95 ages
P11_SP00109 1345
P11_ST00118 1363 69 [32,
P11_SP00110 1432
P11_ST00119 1451 33].
P11_SP00111 1521
P11_ST00120 1552 Thus,
P11_SP00112 1661 1192
P11_ST00121 1681 it
P11_SP00113
P11_ST00122 1717 28
P11_SP00114 1745
P11_ST00123 1763 187 important
P11_SP00115 1950
P11_ST00124 35
P11_SP00116 2000
P11_ST00125 2017 examine
P11_TL00010 1259 1926
P11_ST00126
P11_SP00117
P11_ST00127 380 role
P11_SP00118
P11_ST00128 468 37
P11_SP00119 505
P11_ST00129 114 IL17A
P11_SP00120 635
P11_ST00130 652
P11_SP00121 681
P11_ST00131 698
P11_SP00122 759
P11_ST00132
P11_SP00123 1036 1300
P11_ST00133 1051
P11_SP00124
P11_ST00134 1102
P11_SP00125 1159
P11_ST00135 1176
P11_SP00126
P11_ST00136 1228 89 prior
P11_SP00127 1317
P11_ST00137 1331
P11_SP00128
P11_ST00138 1422 post
P11_SP00129 1505
P11_ST00139 1519
P11_SP00130 1554
P11_ST00140 1571 1267 any
P11_SP00131 1641
P11_ST00141 1659
P11_SP00132 2030
P11_ST00142 179 changes.
P11_TL00011 453 1364 1605
P11_ST00143 Mice
P11_SP00133 544 1396
P11_ST00144 561 138 treated
P11_SP00134 699
P11_ST00145 715
P11_SP00135 793
P11_ST00146 809
P11_SP00136
P11_ST00147 1041 1372
P11_SP00137
P11_ST00148 1092 197 Ad5-LacZ
P11_SP00138 1289
P11_ST00149 1305 1365
P11_SP00139 1341
P11_ST00150 1356
P11_SP00140 1470
P11_ST00151 1484
P11_SP00141
P11_ST00152
P11_SP00142 1597
P11_ST00153 1614
P11_SP00143 1653
P11_ST00154 1670 44
P11_SP00144 1714
P11_ST00155 1729
P11_SP00145 1806
P11_ST00156 1823
P11_SP00146 1860
P11_ST00157 72 age
P11_SP00147 1945
P11_ST00158 1961
P11_TL00012 1792
P11_ST00159 euthanized
P11_SP00148 1501
P11_ST00160 539
P11_SP00149
P11_ST00161 589 47 26
P11_SP00150 636
P11_ST00162
P11_SP00151 725
P11_ST00163 27
P11_SP00152 789
P11_ST00164 804
P11_SP00153 882
P11_ST00165 898
P11_SP00154 936
P11_ST00166 949 1477
P11_SP00155 1032 1510
P11_ST00167 1052 54 i.e.
P11_SP00156 1106 22
P11_ST00168
P11_SP00157 1172
P11_ST00169 1187
P11_SP00158 1264
P11_ST00170 1280
P11_SP00159 1351
P11_ST00171 1373
P11_SP00160 1410
P11_ST00172 1431
P11_SP00161
P11_ST00173 1526 post-treatment, 000000000000000
P11_SP00162 1827
P11_ST00174 1847 respectively.
P11_TL00013 1575 1889
P11_ST00175 246 Splenocytes
P11_SP00163 548 1616
P11_ST00176 1583
P11_SP00164 1607
P11_ST00177 678 isolated
P11_SP00165
P11_ST00178
P11_SP00166 934
P11_ST00179 953 185 individual
P11_SP00167 1138
P11_ST00180 1157
P11_SP00168 1248
P11_ST00181 1265
P11_SP00169 1336
P11_ST00182 1354 194
P11_SP00170 1548
P11_ST00183 1565 53 for
P11_SP00171 1618
P11_ST00184 1631
P11_SP00172 1691
P11_ST00185 1709 number
P11_SP00173 1862
P11_ST00186 1876
P11_SP00174 1914
P11_ST00187 1930 106 IFN-y
P11_SP00175 2036
P11_ST00188 2052
P11_SP00176 2123
P11_ST00189 2143 48 IL-
P11_TL00014 305 1680 1883
P11_ST00190 17A
P11_SP00177 1712
P11_ST00191 396 181 secreting
P11_SP00178 1721
P11_ST00192 595 CD4+T
P11_SP00179 738
P11_ST00193 754 cells.
P11_SP00180 852
P11_ST00194 886 Representative
P11_SP00181 1188
P11_ST00195 1205 data,
P11_SP00182 1719
P11_ST00196 1321 presented
P11_SP00183 1518
P11_ST00197 1537
P11_SP00184 1566
P11_ST00198 1586 160 Figures
P11_SP00185 1746
P11_ST00199 55 2B
P11_SP00186 1818
P11_ST00200 1834 73 &C,
P11_SP00187
P11_ST00201 1927
P11_SP00188 2096
P11_ST00202 2114 74 that
P11_TL00015 1848
P11_ST00203
P11_SP00189
P11_ST00204
P11_SP00190 533
P11_ST00205
P11_SP00191 584
P11_ST00206 129 IL-17A
P11_SP00192 729
P11_ST00207 745
P11_SP00193 926
P11_ST00208 944
P11_SP00194 1087
P11_ST00209 1103 cells
P11_SP00195 1191
P11_ST00210 1209
P11_SP00196 1238
P11_ST00211 1255
P11_SP00197 1315
P11_ST00212 1332 155 spleens
P11_SP00198 1487
P11_ST00213 1503
P11_SP00199
P11_ST00214 1555
P11_SP00200 1646
P11_ST00215 1665 receiving
P11_SP00201 1842
P11_ST00216 1859
P11_SP00202 1919
P11_ST00217 1934
P11_TL00016 1891 1846
P11_ST00218 1892 125
P11_SP00203 426
P11_ST00219 440
P11_SP00204 475
P11_ST00220 491
P11_SP00205 512
P11_ST00221 527
P11_SP00206 604
P11_ST00222 620
P11_SP00207
P11_ST00223 671 1899
P11_SP00208 743 1932
P11_ST00224 79 was
P11_SP00209 838
P11_ST00225 281 approximately
P11_SP00210 1136
P11_ST00226 1152 2-fold
P11_SP00211 1262
P11_ST00227 1281 126 higher
P11_SP00212 1407
P11_ST00228 than
P11_SP00213 1504
P11_ST00229 1524
P11_SP00214 1615
P11_ST00230 1633
P11_SP00215 1810
P11_ST00231
P11_SP00216 1887
P11_ST00232 1905 control
P11_SP00217 2037
P11_ST00233 2053 94 Ad5-
P11_TL00017 1997
P11_ST00234 96 LacZ
P11_SP00218 400 2029
P11_ST00235 416 1998 vector,
P11_SP00219
P11_ST00236 102 while
P11_SP00220
P11_ST00237 683
P11_SP00221
P11_ST00238 761
P11_SP00222 915
P11_ST00239 929
P11_SP00223
P11_ST00240 982
P11_SP00224 1088 2038
P11_ST00241 1104
P11_SP00225 1285
P11_ST00242 1303 144
P11_SP00226 1447
P11_ST00243 1462
P11_SP00227 1550
P11_ST00244 2005
P11_SP00228 1644
P11_ST00245
P11_SP00229
P11_ST00246 1960 half
P11_SP00230 2032
P11_ST00247 2046
P11_SP00231 2081
P11_ST00248
P11_SP00232 2179
P11_ST00249 2196
P11_TL00018 2102
P11_ST00250 172 analysis.
P11_SP00233 474
P11_ST00251 506 Similarly,
P11_SP00234 685
P11_ST00252 703
P11_SP00235 2134
P11_ST00253 782
P11_SP00236 935
P11_ST00254
P11_SP00237 986
P11_ST00255 1002
P11_SP00238 1132
P11_ST00256 1148 180
P11_SP00239 1328
P11_ST00257 1347
P11_SP00240 1490
P11_ST00258 1506 87
P11_SP00241 1593
P11_ST00259 1611
P11_SP00242
P11_ST00260 1658
P11_SP00243
P11_ST00261 1735
P11_SP00244
P11_ST00262 1906
P11_SP00245 1943
P11_ST00263
P11_SP00246 2049
P11_ST00264 2067
P11_TL00019 2207 1918
P11_ST00265
P11_SP00247 2239
P11_ST00266 377
P11_SP00248 592
P11_ST00267 607 2208
P11_SP00249 731
P11_ST00268
P11_SP00250 781
P11_ST00269 799
P11_SP00251 843
P11_ST00270 858
P11_SP00252
P11_ST00271 952
P11_SP00253 989
P11_ST00272 1003 2215
P11_SP00254 1075 2248
P11_ST00273
P11_SP00255 1169
P11_ST00274 1186
P11_SP00256 1467
P11_ST00275 7-fold
P11_SP00257
P11_ST00276 1613
P11_SP00258 1738
P11_ST00277 1751 85
P11_SP00259 1836
P11_ST00278 1855
P11_SP00260 1946
P11_ST00279 1964
P11_SP00261 2141
P11_ST00280 2159
P11_TL00020 2313
P11_ST00281
P11_SP00262 434 2345
P11_ST00282
P11_SP00263 647
P11_ST00283 663 2314
P11_SP00264 795 2352
P11_ST00284 812
P11_SP00265 914
P11_ST00285 930
P11_SP00266 990
P11_ST00286 1009
P11_SP00267 1162
P11_ST00287
P11_SP00268 1213
P11_ST00288 1229
P11_SP00269 1335 2354
P11_ST00289 1352
P11_SP00270 1532
P11_ST00290
P11_SP00271 1694
P11_ST00291
P11_SP00272 1797
P11_ST00292 1812 2321
P11_SP00273
P11_ST00293 less
P11_SP00274 1986
P11_ST00294 2001
P11_SP00275 2086
P11_ST00295 2104 86 50%
P11_SP00276 2190
P11_ST00296 2209
P11_TL00021 2418 1886
P11_ST00297
P11_SP00277 384 2450
P11_ST00298 401
P11_SP00278 439
P11_ST00299 452 162 analysis
P11_SP00279 614 2459
P11_ST00300 632 149 (Figure
P11_SP00280
P11_ST00301 51 2E
P11_SP00281 850
P11_ST00302 867 30 &
P11_SP00282 897
P11_ST00303 49 F).
P11_SP00283 963
P11_ST00304 147 Results
P11_SP00284 1144
P11_ST00305 1160
P11_SP00285
P11_ST00306 1211 2426 a
P11_SP00286 1232
P11_ST00307 similar
P11_SP00287 1381
P11_ST00308 1395 161
P11_SP00288 1556
P11_ST00309
P11_SP00289 1649
P11_ST00310 1668 untreated
P11_SP00290
P11_ST00311 1875
P11_SP00291 1966
P11_ST00312 1984 203 performed
P11_TL00022 2524 1908
P11_ST00313 2532 one
P11_SP00292 374 2556
P11_ST00314 389 wk
P11_SP00293 444
P11_ST00315 461
P11_SP00294 2565
P11_ST00316 2525
P11_SP00295 598
P11_ST00317
P11_SP00296
P11_ST00318 753 253 cannulations
P11_SP00297 1006
P11_ST00319 1023
P11_SP00298 1085
P11_ST00320
P11_SP00299
P11_ST00321 1320
P11_SP00300 1349
P11_ST00322 1368
P11_SP00301 1528
P11_ST00323 1545 2A
P11_SP00302 1600
P11_ST00324 1617
P11_SP00303 1647
P11_ST00325 1663 D.
P11_SP00304 1702
P11_ST00326 1720 These
P11_SP00305 1844
P11_ST00327 1861 data
P11_SP00306
P11_ST00328 1963 158 suggest
P11_SP00307 2121
P11_ST00329 2135
P11_TL00023 2629 1779
P11_ST00330 2637 even
P11_SP00308 2661
P11_ST00331 413 136 though
P11_SP00309 549 2670
P11_ST00332 566
P11_SP00310
P11_ST00333 641 Ad5
P11_SP00311 720
P11_ST00334 737 2630
P11_SP00312 861
P11_ST00335 876
P11_SP00313 904
P11_ST00336 921 considered
P11_SP00314
P11_ST00337 123 locally
P11_SP00315
P11_ST00338 1299 restricted,
P11_SP00316 1493 2668
P11_ST00339 1511
P11_SP00317
P11_ST00340 1589 effect
P11_SP00318 1698
P11_ST00341 1715
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P30_ST00144 167 spleens
P30_SP00134 2128
P30_ST00145 2145
P30_TL00012 1680 1908
P30_ST00146 391 Ad5-IL17A-treated 00000000000000000
P30_SP00135 691 1712
P30_ST00147 711 109 mice.
P30_SP00136 820
P30_ST00148 852 149 Splenic
P30_SP00137 1001 1721
P30_ST00149 1016 212 leukocytes
P30_SP00138 1228
P30_ST00150 1246
P30_SP00139 1422
P30_ST00151 1440
P30_SP00140 1527
P30_ST00152 1545 196 0.93 00000400
P30_SP00141
P30_ST00153 1760
P30_SP00142 1852
P30_ST00154 1870
P30_SP00143 1972
P30_ST00155 1990 1681
P30_SP00144 2025
P30_ST00156 2040 22 6
P30_SP00145 2062
P30_ST00157 2077 wks
P30_SP00146 2154
P30_ST00158 2171
P30_TL00013 1786 1718
P30_ST00159 72 age
P30_SP00147 374 1827
P30_ST00160 392 86 (one
P30_SP00148 478
P30_ST00161 494
P30_SP00149 549 1818
P30_ST00162 565
P30_SP00150 655
P30_ST00163 668 1787
P30_SP00151 703
P30_ST00164 719
P30_SP00152 843
P30_ST00165 205 treatment)
P30_SP00153 1061
P30_ST00166 1079
P30_SP00154 1150
P30_ST00167 1167 48 26
P30_SP00155 1215
P30_ST00168 1230
P30_SP00156
P30_ST00169 1323
P30_SP00157 1379
P30_ST00170 1398 (19
P30_SP00158 1459
P30_ST00171
P30_SP00159 1551
P30_ST00172 83 post
P30_SP00160 1652
P30_ST00173
P30_SP00161 1791
P30_ST00174 216 treatment), 00000000000
P30_TL00014 1912
P30_ST00175 219 considered
P30_SP00162 1923
P30_ST00176 539 95 early
P30_SP00163
P30_ST00177 650
P30_SP00164 842
P30_ST00178 (A-C),
P30_SP00165 975
P30_ST00179 1899
P30_SP00166 1034
P30_ST00180 141 splenic
P30_SP00167
P30_ST00181
P30_SP00168 1416
P30_ST00182 1434
P30_SP00169 1611
P30_ST00183
P30_SP00170 1716
P30_ST00184 1734 195
P30_SP00171 1929
P30_ST00185 1949
P30_SP00172
P30_ST00186 2058
P30_SP00173 2160
P30_ST00187 2178 36
P30_TL00015 305 1997 1921
P30_ST00188 43
P30_SP00174 2029
P30_ST00189 364
P30_SP00175 441
P30_ST00190
P30_SP00176 495
P30_ST00191 508 2005
P30_SP00177 580 2038
P30_ST00192 598
P30_SP00178 685
P30_ST00193 700
P30_SP00179 755
P30_ST00194 772 89
P30_SP00180 861
P30_ST00195 874 1998
P30_SP00181 909
P30_ST00196 925
P30_SP00182 1050
P30_ST00197
P30_SP00183
P30_ST00198 1285
P30_SP00184
P30_ST00199 27
P30_SP00185 1421
P30_ST00200 1436
P30_SP00186 1513
P30_ST00201 1530
P30_SP00187 1585
P30_ST00202 1605 29 (1
P30_SP00188 1634
P30_ST00203 1647
P30_SP00189 1659
P30_ST00204
P30_SP00190 1758
P30_ST00205 1775
P30_SP00191
P30_ST00206 1873
P30_SP00192
P30_ST00207 2010
P30_TL00016 2102 1937
P30_ST00208
P30_SP00193 2134
P30_ST00209 540 68 late
P30_SP00194 608
P30_ST00210 625 2103
P30_SP00195
P30_ST00211 833 (D-F)
P30_SP00196 934 2143
P30_ST00212 2110
P30_SP00197 1046
P30_ST00213 1064 examined
P30_SP00198 1257
P30_ST00214 1274 53
P30_SP00199
P30_ST00215 1340
P30_SP00200 1401
P30_ST00216 1419 183 presence
P30_SP00201 1602
P30_ST00217 1619
P30_SP00202 1657
P30_ST00218 1671 232 intracellular
P30_SP00203 1903
P30_ST00219 1919 130
P30_SP00204 2049
P30_ST00220 2065
P30_SP00205 2136
P30_ST00221 2156 IFN-
P30_TL00017 2201 1806
P30_ST00222 2216 Y
P30_SP00206 321 2248
P30_ST00223 2207 gated
P30_SP00207 447
P30_ST00224 2215
P30_SP00208 511 2239
P30_ST00225 134 0007100
P30_SP00209 663
P30_ST00226 678
P30_SP00210 766
P30_ST00227 782 173
P30_SP00211 955
P30_ST00228 a
P30_SP00212
P30_ST00229 1012
P30_SP00213 1033
P30_ST00230 1051 hr
P30_SP00214
P30_ST00231 in-vitro 00000001
P30_SP00215 1238
P30_ST00232 1254 188 activation
P30_SP00216 1442
P30_ST00233 1458
P30_SP00217 1536
P30_ST00234 1554 anti-CD3£ 000000005
P30_SP00218 1752
P30_ST00235 1769
P30_SP00219 1840
P30_ST00236 202 anti-CD28
P30_SP00220 2060
P30_ST00237 2078
P30_TL00018 2313
P30_ST00238 Leukocyte
P30_SP00221 2354
P30_ST00239 522 Activation
P30_SP00222 717 2345
P30_ST00240 735 158 Cocktail
P30_SP00223 893
P30_ST00241 911
P30_SP00224 1114
P30_ST00242 1133 GolgiPlug.
P30_SP00225 1337
P30_ST00243 1371 Flow
P30_SP00226 1464
P30_ST00244 1479 207 cytometric
P30_SP00227
P30_ST00245 1701 acquisition
P30_SP00228
P30_ST00246 1928 2321 79 was
P30_SP00229 2007
P30_ST00247 performed
P30_TL00019 2418 1842
P30_ST00248
P30_SP00230 346 2459
P30_ST00249
P30_SP00231 516
P30_ST00250 532
P30_SP00232 610 2450
P30_ST00251 390 PE-Cy5-conjugated
P30_SP00233 1020
P30_ST00252 1039 2419 rat
P30_SP00234
P30_ST00253 1105 186 anti-CD4,
P30_SP00235 2457
P30_ST00254 1313 334 FITC-conjugated
P30_SP00236
P30_ST00255
P30_SP00237
P30_ST00256 1731 anti-IFNy
P30_SP00238 1913
P30_ST00257 1930 129 andor 000400
P30_SP00239 2059
P30_ST00258 2075 PE-
P30_TL00020 2524 1941
P30_ST00259 conjugated
P30_SP00240 2565
P30_ST00260 2525
P30_SP00241 590 2556
P30_ST00261 605 230 anti-IL-17A.
P30_SP00242 835
P30_ST00262 870 Data
P30_SP00243 960
P30_ST00263 2532
P30_SP00244 1055
P30_ST00264 1071 analyzed
P30_SP00245
P30_ST00265 1269
P30_SP00246
P30_ST00266 1331 FCS 0.97
P30_SP00247
P30_ST00267 1435 170 Express.
P30_SP00248
P30_ST00268 1626
P30_SP00249 1719
P30_ST00269
P30_SP00250
P30_ST00270 1956 images
P30_SP00251 2099
P30_ST00271 2116 127 shown
P30_TL00021 2629 1872
P30_ST00272 2637 are
P30_SP00252 2661
P30_ST00273 380
P30_SP00253 467
P30_ST00274 485 one
P30_SP00254 557
P30_ST00275 576 285 representative
P30_SP00255 2670
P30_ST00276 161 analysis
P30_SP00256
P30_ST00277
P30_SP00257 1094
P30_ST00278 1106 2
P30_SP00258 1127
P30_ST00279 1146 249 independent
P30_SP00259 1395
P30_ST00280 1410 246 experiments
P30_SP00260 1656
P30_ST00281 1672 74 that
P30_SP00261
P30_ST00282 1762
P30_SP00262
P30_ST00283
P30_SP00263 1993
P30_ST00284 2011 163 different
P30_TL00022 2734 1920
P30_ST00285
P30_SP00264 2766
P30_ST00286 within
P30_SP00265 523
P30_ST00287 541
P30_SP00266 635
P30_ST00288 654 experiment.
P30_SP00267 886 2775
P30_ST00289 921
P30_SP00268 1011
P30_ST00290 1029 presented
P30_SP00269 1227
P30_ST00291 2742 as
P30_SP00270 1289
P30_ST00292 108 mean
P30_SP00271 1415
P30_ST00293 1433 2739 +
P30_SP00272 1455 2761
P30_ST00294 1473 SEM
P30_SP00273 1566
P30_ST00295
P30_SP00274 1637
P30_ST00296 n 4
P30_SP00275 1724
P30_ST00297 1743 64 per
P30_SP00276 1807
P30_ST00298 112
P30_SP00277 1933
P30_ST00299 1950
P30_SP00278 2021
P30_ST00300 statistical
P30_TL00023 2840 1931
P30_ST00301 analyses
P30_SP00279 479 2881
P30_ST00302 2848
P30_SP00280 591 2872
P30_ST00303 609
P30_SP00281 811
P30_ST00304 829 209 comparing
P30_SP00282 1038
P30_ST00305
P30_SP00283 1115
P30_ST00306 1134 means
P30_SP00284 1266
P30_ST00307 1283
P30_SP00285
P30_ST00308 1333
P30_SP00286
P30_ST00309 1408 172 Ad-LacZ
P30_SP00287 1580
P30_ST00310 1596
P30_SP00288 1667
P30_ST00311 1683 190 Ad-IL17A
P30_SP00289
P30_ST00312 1888 treated
P30_SP00290 2027
P30_ST00313 2045 groups
P30_SP00291 2181
P30_ST00314 2198 2841
P30_TB00003 3047
P30_TL00024 3053
P30_ST00315


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Description
MeasurementUnit pixel
sourceImageInformation
fileName Z:\Scan\Mariner\IR SS\OCR\IR00000341_00001\NguyenCQ_Manuscript_IRUF_Page_04.tif
OCRProcessing ID OCRPROCESSING_1
preProcessingStep
processingSoftware
softwareCreator Kirtas Technologies, Inc.
softwareName BookScan Editor
softwareVersion 3.6
ocrProcessingStep
Kirtas Technologies, Inc.
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Page P4 PHYSICAL_IMG_NR 4 HEIGHT 3300 WIDTH 2550
TopMargin P4_TM00001 HPOS 0 VPOS 304
LeftMargin P4_LM00001 296 2785
RightMargin P4_RM00001 2230 320
BottomMargin P4_BM00001 3089 211
PrintSpace P4_PS00001 1934
TextBlock P4_TB00001 1845
TextLine P4_TL00001 302 310 1873 41
String P4_ST00001 140 32 CONTENT distinct WC 1.00 CC 00000000
SP P4_SP00001 442 342 14
P4_ST00002 456 99 39 from, 00000
P4_SP00002 555 349 19
P4_ST00003 574 71 and 000
P4_SP00003 645 20
P4_ST00004 665 184 unrelated 000000000
P4_SP00004 849 17
P4_ST00005 866 311 46 38 to,
P4_SP00005 912
P4_ST00006 931 114 either 000000
P4_SP00006 1045 12
P4_ST00007 1057 61 the
P4_SP00007 1118 16
P4_ST00008 1134 65 ThI
P4_SP00008 1199 348 23
P4_ST00009 1222 123 orTH2
P4_SP00009 1345 18
P4_ST00010 1363 64 cell 0000
P4_SP00010 1427
P4_ST00011 1446 165 lineages
P4_SP00011 1611 351
P4_ST00012 1629 148 [10-14].
P4_SP00012 1777 31
P4_ST00013 1808
P4_SP00013 11
P4_ST00014 1884 21 7 0.63 3
P4_SP00014 1905
P4_ST00015 1922 151 effector
P4_SP00015 2073
P4_ST00016 2087 88 cells
P4_TL00002 415 1871
P4_ST00017 416 146 secrete 0000000
P4_SP00016 448 447
P4_ST00018 465 36 at 00
P4_SP00017 501
P4_ST00019 517 93 least
P4_SP00018 610
P4_ST00020 626 423 72 24 one
P4_SP00019 698
P4_ST00021 715 37 of
P4_SP00020 752 13
P4_ST00022 765 60
P4_SP00021 825
P4_ST00023 842 53 six
P4_SP00022 895
P4_ST00024 911 187 cytokines
P4_SP00023 1098
P4_ST00025 1116 192 belonging
P4_SP00024 1308
P4_ST00026 1325 35 to
P4_SP00025 1360
P4_ST00027 1376
P4_SP00026 1437
P4_ST00028 1456 98 IL-17
P4_SP00027 1554
P4_ST00029 1570 127 family,
P4_SP00028 1697
P4_ST00030 1717 66 i.e.,
P4_SP00029 1783 454 22
P4_ST00031 1805 139 IL-17A,
P4_SP00030 1944
P4_ST00032 1965 IL-17B,
P4_SP00031 2104
P4_ST00033 2126 47 IL-
P4_TL00003 305 521 1850
P4_ST00034 87 17C, 0.98
P4_SP00032 392 560
P4_ST00035 414 141 IL-17D,
P4_SP00033
P4_ST00036 577 IL-25
P4_SP00034 675 553
P4_ST00037 692 128 andor 0.93 000400
P4_SP00035 820
P4_ST00038 836 137 IL-17F;
P4_SP00036 973
P4_ST00039 993 179 however,
P4_SP00037 1172
P4_ST00040 1193
P4_SP00038 1332
P4_ST00041 1351
P4_SP00039 1411
P4_ST00042 1428 signature
P4_SP00040 1612 562
P4_ST00043 1630 174 cytokine,
P4_SP00041 1804
P4_ST00044 1824 69 has
P4_SP00042 1893
P4_ST00045 1911 166 received
P4_SP00043 2077
P4_ST00046 2095
P4_TL00004 1889
P4_ST00047 627 163 40 greatest
P4_SP00044 667 15
P4_ST00048 480 171 attention
P4_SP00045 651 658
P4_ST00049 670 29 in
P4_SP00046 699
P4_ST00050 717 142 studies
P4_SP00047 859
P4_ST00051 875
P4_SP00048 913
P4_ST00052 926 248 autoimmune 0000000000
P4_SP00049 1174
P4_ST00053 1191 177 diseases
P4_SP00050 1368
P4_ST00054 1386 81 [15].
P4_SP00051 1467 44
P4_ST00055 1511 76 The
P4_SP00052 1587
P4_ST00056 1606 I
P4_SP00053 1610 9
P4_ST00057 1619 LI
P4_SP00054 1657
P4_ST00058 1668
P4_SP00055 1689
P4_ST00059 1706
P4_SP00056
P4_ST00060 1910 634 62 are
P4_SP00057 1972
P4_ST00061 1990 124 potent
P4_SP00058 2114
P4_ST00062 2130 33 pro SUBS_TYPE HypPart1 SUBS_CONTENT proinflammatory
P4_TL00005 303 732 1686
P4_ST00063 258 inflammatory 000000000000 HypPart2
P4_SP00059 561 773
P4_ST00064 578 212 molecules,
P4_SP00060 790 771
P4_ST00065 809 149 actively
P4_SP00061 958
P4_ST00066 976 161 involved
P4_SP00062 1137 764
P4_ST00067 1157
P4_SP00063 1186
P4_ST00068 1203 116 tissue
P4_SP00064 1319
P4_ST00069 1338 253 inflammation
P4_SP00065 1591
P4_ST00070 1608 55 via
P4_SP00066 1663
P4_ST00071 1681 induction
P4_SP00067 1858
P4_ST00072 1877
P4_SP00068 1914
P4_ST00073 1928 740
P4_TL00006 837 1839
P4_ST00074
P4_SP00069 878
P4_ST00075 164 cytokine
P4_SP00070 741
P4_ST00076 758
P4_SP00071 829 869
P4_ST00077 847 217 chemokine
P4_SP00072 1064
P4_ST00078 1082 240 expressions 00000000000
P4_SP00073 1322
P4_ST00079 1340 [16].
P4_SP00074 1421
P4_ST00080 30 In
P4_SP00075 1486
P4_ST00081 1505 addition,
P4_SP00076 1671 876
P4_ST00082 1693
P4_SP00077 1791
P4_ST00083 1809 28 is
P4_SP00078 1837
P4_ST00084 1855
P4_SP00079 2016
P4_ST00085 2036
P4_SP00080 2065
P4_ST00086 2082
P4_TL00007 942 1896
P4_ST00087 247 mobilization, 0000000000000
P4_SP00081 550 981
P4_ST00088 571 210 maturation
P4_SP00082 781 974
P4_ST00089 799
P4_SP00083 870
P4_ST00090 889 182 migration
P4_SP00084 1071 983
P4_ST00091 1089
P4_SP00085 1127
P4_ST00092 1141 220 neutrophils
P4_SP00086 1361
P4_ST00093 56
P4_SP00087 1432
P4_ST00094 1448
P4_SP00088 1508
P4_ST00095 1526 145 release
P4_SP00089
P4_ST00096 1688
P4_SP00090 1726
P4_ST00097 1741 IL-8
P4_SP00091 1813
P4_ST00098 1831 943
P4_SP00092 1866
P4_ST00099 1881
P4_SP00093 1941
P4_ST00100 1958 67 site
P4_SP00094 2025
P4_ST00101 2042
P4_SP00095 2080
P4_ST00102 2094 105 injury
P4_TL00008 1048 1711
P4_ST00103 [17].
P4_SP00096 384
P4_ST00104 419 251 Interestingly, 00000000000000
P4_SP00097
P4_ST00105 691 130 IL-17A
P4_SP00098 821 1080
P4_ST00106 838
P4_SP00099
P4_ST00107 884 126 known
P4_SP00100 1010
P4_ST00108 1027 1049
P4_SP00101 1062
P4_ST00109 160 regulate
P4_SP00102 1240
P4_ST00110 1259 Foxp3+
P4_SP00103 1407
P4_ST00111 1423 79 TReg 0.92 0030
P4_SP00104 1502 1092
P4_ST00112 1519
P4_SP00105
P4_ST00113 1623
P4_SP00106 1694
P4_ST00114 78 vice
P4_SP00107 1789
P4_ST00115 1056 109 versa
P4_SP00108
P4_ST00116 1932 82 [18].
P4_TL00009 451 1153 1729
P4_ST00117 111 While
P4_SP00109 1185
P4_ST00118
P4_SP00110 643
P4_ST00119 654
P4_SP00111
P4_ST00120
P4_SP00112 780
P4_ST00121 798 have
P4_SP00113 891
P4_ST00122 910 95 been
P4_SP00114 1005
P4_ST00123 1024 200 implicated
P4_SP00115 1224 1194
P4_ST00124 1243
P4_SP00116 1273
P4_ST00125 1291 143 several
P4_SP00117 1434
P4_ST00126 1451
P4_SP00118 1699
P4_ST00127 1716
P4_SP00119
P4_ST00128 97 (e.g.,
P4_SP00120 2008
P4_ST00129 2027 153 Crohn's 0.99
P4_TL00010 1844
P4_ST00130 154 disease
P4_SP00121
P4_ST00131 474 68 [19,
P4_SP00122 542 1300
P4_ST00132 20],
P4_SP00123 632
P4_ST00133 257 experimental
P4_SP00124 908
P4_ST00134
P4_SP00125
P4_ST00135 1192 360 encephalomyelitis 00000000000000000
P4_SP00126 1552
P4_ST00136 (EAE)
P4_SP00127
P4_ST00137 1704 [21],
P4_SP00128 1786
P4_ST00138 341 collagen-induced 0000000000000000
P4_TL00011 1364 1863
P4_ST00139 arthritis
P4_SP00129 1396
P4_ST00140 86 CIA)
P4_SP00130 551 1405
P4_ST00141 570
P4_SP00131 652
P4_ST00142 671 57 SS
P4_SP00132 728
P4_ST00143 746 45 [8]
P4_SP00133 791
P4_ST00144
P4_SP00134 880
P4_ST00145 898 others
P4_SP00135 1022
P4_ST00146 1039 43 [2,
P4_SP00136
P4_ST00147 1102 59 3]),
P4_SP00137 1161
P4_ST00148 1180 this
P4_SP00138 1248
P4_ST00149 1265 268 characteristic
P4_SP00139 1533
P4_ST00150 1549 1372 may
P4_SP00140
P4_ST00151 1648 require
P4_SP00141 1785
P4_ST00152 1802 176 signaling
P4_SP00142 1978
P4_ST00153 1995 from
P4_SP00143
P4_ST00154 2099
P4_TL00012 1469 1917
P4_ST00155
P4_SP00144 390 1501
P4_ST00156 406 147 already
P4_SP00145 1510
P4_ST00157 1470 present
P4_SP00146 720
P4_ST00158 736
P4_SP00147
P4_ST00159 783
P4_SP00148 843
P4_ST00160 861 113 lesion
P4_SP00149
P4_ST00161 [3].
P4_SP00150
P4_ST00162 1084
P4_SP00151 1114
P4_ST00163 1133 1477 70 any
P4_SP00152
P4_ST00164 1219 118 event,
P4_SP00153 1337
P4_ST00165 1358 recent
P4_SP00154 1481
P4_ST00166 1497 267 observational
P4_SP00155 1764
P4_ST00167 1782
P4_SP00156 1924
P4_ST00168
P4_SP00157 1970
P4_ST00169 1989
P4_SP00158 2045
P4_ST00170 2064 155 patients
P4_TL00013 1575
P4_ST00171
P4_SP00159 373 1607
P4_ST00172 391 animal
P4_SP00160
P4_ST00173 540 models
P4_SP00161 683
P4_ST00174
P4_SP00162 737
P4_ST00175 751 primary
P4_SP00163 899 1616
P4_ST00176 916
P4_SP00164
P4_ST00177 991 94
P4_SP00165 1085
P4_ST00178 1103 identified
P4_SP00166 1280
P4_ST00179 1297
P4_SP00167 1357
P4_ST00180 1583 183 presence
P4_SP00168 1559
P4_ST00181 1576
P4_SP00169 1613
P4_ST00182 129
P4_SP00170 1758
P4_ST00183 1775
P4_SP00171 1846
P4_ST00184 1865 its
P4_SP00172 1906
P4_ST00185 189 activating
P4_TL00014 1680 1867
P4_ST00186
P4_SP00173 466 1721
P4_ST00187 485 IL-23
P4_SP00174 583 1712
P4_ST00188 601
P4_SP00175 630
P4_ST00189 647
P4_SP00176 708
P4_ST00190 726 236 lymphocytic
P4_SP00177 962
P4_ST00191 978 infiltrates
P4_SP00178
P4_ST00192 1173
P4_SP00179 1211
P4_ST00193 1223
P4_SP00180 1283
P4_ST00194 1301 168 exocrine
P4_SP00181
P4_ST00195 1487 glands,
P4_SP00182 1628
P4_ST00196 1647 as
P4_SP00183 1692
P4_ST00197 well
P4_SP00184
P4_ST00198 1800
P4_SP00185
P4_ST00199 1862 125 higher
P4_SP00186 1987
P4_ST00200 2002 112 levels
P4_SP00187
P4_ST00201 2131
P4_TL00015 1903
P4_ST00202 201 circulating
P4_SP00188 503 1827
P4_ST00203 523
P4_SP00189 653 1818
P4_ST00204
P4_SP00190
P4_ST00205 718 83 both
P4_SP00191 801
P4_ST00206 819 1794 85 sera
P4_SP00192 904
P4_ST00207 921
P4_SP00193 992
P4_ST00208 saliva
P4_SP00194 1123
P4_ST00209 [8],
P4_SP00195 1197
P4_ST00210 1218 raising
P4_SP00196 1346
P4_ST00211
P4_SP00197 1424
P4_ST00212 1441 question
P4_SP00198 1609
P4_ST00213 1627
P4_SP00199 1665
P4_ST00214 1677
P4_SP00200 1737
P4_ST00215 1756 221 importance 0000010000
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P4_ST00216 1994
P4_SP00202 2032 27
P4_ST00217 2059
P4_SP00203 2157
P4_ST00218 2176
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P4_ST00219 SS.
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P4_ST00220 400 Thus,
P4_SP00205 509 1930
P4_ST00221 528
P4_SP00206 588
P4_ST00222 605 106 goals
P4_SP00207 711
P4_ST00223
P4_SP00208
P4_ST00224 778
P4_SP00209
P4_ST00225 856 1892
P4_SP00210
P4_ST00226 1021 study
P4_SP00211 1126
P4_ST00227 1899 were
P4_SP00212 1238
P4_ST00228 1254
P4_SP00213 1289
P4_ST00229 1306 determine
P4_SP00214 1506
P4_ST00230 1521 whether
P4_SP00215 1685
P4_ST00231 1700
P4_SP00216 1830
P4_ST00232 can
P4_SP00217
P4_ST00233 1933 directly
P4_TL00017 1997 1921
P4_ST00234 178 influence
P4_SP00218 481 2029
P4_ST00235 497
P4_SP00219 557
P4_ST00236 576 193 pathology
P4_SP00220 769 2038
P4_ST00237 787 leading
P4_SP00221 929
P4_ST00238 946 1998 34
P4_SP00222 980
P4_ST00239 997
P4_SP00223
P4_ST00240 1074 110 onset
P4_SP00224 1184
P4_ST00241
P4_SP00225 1237
P4_ST00242 1250 SS-like
P4_SP00226 1391
P4_ST00243 1408
P4_SP00227 1561
P4_ST00244 1580 by
P4_SP00228
P4_ST00245 1640 280 administrating
P4_SP00229 1920
P4_ST00246 1938 2005 exogenous
P4_SP00230 2158
P4_ST00247 2177
P4_TL00018 2102 979
P4_ST00248 75 17A
P4_SP00231 380 2134
P4_ST00249 395 2103
P4_SP00232 430
P4_ST00250 446
P4_SP00233 507
P4_ST00251 524 salivary
P4_SP00234 2143
P4_ST00252 131 glands
P4_SP00235 823
P4_ST00253 840
P4_SP00236
P4_ST00254 specific
P4_SP00237 1042
P4_ST00255 1055 time
P4_SP00238 1138
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P28_ST00008 1124 77 She
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P28_ST00009 1218 60 JX,
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P28_SP00010 1469
P28_ST00011 1488 RA,
P28_SP00011 1556
P28_ST00012 1577 97 Peck 0000
P28_SP00012 1674 14
P28_ST00013 1688 69 AB:
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P28_ST00017 708 in
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P28_ST00031 1176
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P28_ST00032 1230 67
P28_SP00030
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P28_ST00034 1860 529 153 24 mouse.
P28_SP00032 2013
P28_ST00035 2030 155 Arthritis 0.95 004000000
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P28_ST00036 80 Res
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P28_ST00037 550 93 Ther 0.98
P28_SP00034 643 22
P28_ST00038 665 109 2009,
P28_SP00035 774
P28_ST00039 795 152 11:R56.
P28_TL00005 732 1931
P28_ST00040 33.
P28_SP00036 764
P28_ST00041
P28_SP00037 773
P28_ST00042
P28_SP00038 771
P28_ST00043
P28_SP00039
P28_ST00044
P28_SP00040
P28_ST00045 946 0.99
P28_SP00041 1023
P28_ST00046 1039 61
P28_SP00042 1100
P28_ST00047 1120 171
P28_SP00043 1291
P28_ST00048 1310
P28_SP00044 1378
P28_ST00049 1399
P28_SP00045 1496
P28_ST00050 1510
P28_SP00046 1579
P28_ST00051 1599 233
P28_SP00047 1832
P28_ST00052 1851 740
P28_SP00048 1953
P28_ST00053 1969 264 expressions
P28_TL00006 453 837 1747
P28_ST00054 34
P28_SP00049 487 869
P28_ST00055 503
P28_SP00050 570
P28_ST00056 588 167 lacrimal
P28_SP00051 755
P28_ST00057
P28_SP00052 889 878
P28_ST00058 908
P28_SP00053 1045
P28_ST00059 1063
P28_SP00054 1343
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P28_SP00055 1434
P28_ST00061 1453
P28_SP00056 1572
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P28_ST00063 1645 427 keratoconjunctivitis 00000000000000000000
P28_SP00058 2072
P28_ST00064 2089 111 sicca
P28_TL00007 942 1743
P28_ST00065
P28_SP00059 974
P28_ST00066 505
P28_SP00060 983
P28_ST00067 724 216 syndrome
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P28_ST00068 957 204 (SJS)-like
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P28_ST00069 1179 163
P28_SP00063 1342
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P28_ST00076 635
P28_SP00069 715 1080
P28_ST00077 729
P28_SP00070 838 1087
P28_ST00078 857 238 88:398-409.
P28_TL00009 1153 1905
P28_ST00079 34.
P28_SP00071 1185
P28_ST00080 130 Bettelli
P28_SP00072 584
P28_ST00081 604 35 E,
P28_SP00073 639 1192
P28_ST00082 660 90 Korn
P28_SP00074 750
P28_ST00083 767 T,
P28_SP00075 802
P28_ST00084 821 128 Oukka
P28_SP00076 949
P28_ST00085 968 43 M,
P28_SP00077 1011
P28_ST00086 1032 165 Kuchroo
P28_SP00078 1197
P28_ST00087 1213 VK:
P28_SP00079 1281
P28_ST00088 1301 199 Induction
P28_SP00080 1500
P28_ST00089 1518
P28_SP00081
P28_ST00090 1612 169 effector
P28_SP00082 1781 11
P28_ST00091 1792 functions
P28_SP00083 1996
P28_ST00092
P28_SP00084 2055
P28_ST00093 2069 138 T(H)17
P28_TL00010 1259 720
P28_ST00094 108 cells.
P28_SP00085 560
P28_ST00095 579 134 Nature
P28_SP00086 713
P28_ST00096 2008,
P28_SP00087 1298
P28_ST00097 856 316 453:1051-1057. 00000000000000
P28_TL00011 1364 1907
P28_ST00098 35.
P28_SP00088 1396 92
P28_ST00099 125 Zheng
P28_SP00089 576 1405
P28_ST00100 595 C,
P28_SP00090 634 1403
P28_ST00101 652 Voutetakis 0010000000
P28_SP00091 863
P28_ST00102
P28_SP00092 917
P28_ST00103 938 Kok
P28_SP00093 1012
P28_ST00104 1029 MR,
P28_SP00094
P28_ST00105 201 Goldsmith
P28_SP00095 1325
P28_ST00106 1344 CM,
P28_SP00096 1421
P28_ST00107 1440 112 Smith
P28_SP00097 1552
P28_ST00108 1570 72 GB,
P28_SP00098 1642
P28_ST00109 1664 139 Elmore
P28_SP00099 1803
P28_ST00110 1820 36 S,
P28_SP00100 1856
P28_ST00111 1878 121 Nyska
P28_SP00101 1999
P28_ST00112 2014
P28_SP00102 2053
P28_ST00113 2071 Valiant
P28_TL00012 1513
P28_ST00114
P28_SP00103 496 1508
P28_ST00115 518 89 Irwin
P28_SP00104 607 1501
P28_ST00116 627 RD,
P28_SP00105
P28_ST00117 719 Baum
P28_SP00106 831
P28_ST00118 851 58 BJ:
P28_SP00107 909
P28_ST00119 928 Toxicity
P28_SP00108 1098
P28_ST00120 1113
P28_SP00109 1190
P28_ST00121 1209 314 biodistribution 000000000000000
P28_SP00110 1523
P28_ST00122 1542
P28_SP00111 1584
P28_ST00123 1597 1477 a
P28_SP00112 1619
P28_ST00124 1634 332 first-generation 0000000000000000
P28_TL00013 1575 1758
P28_ST00125 271 recombinant
P28_SP00113 1607
P28_ST00126 739 224 adenoviral
P28_SP00114 963
P28_ST00127 981 146 vector,
P28_SP00115 1127 1614
P28_ST00128 1146
P28_SP00116 1180
P28_ST00129
P28_SP00117 1263
P28_ST00130 1583 196 presence
P28_SP00118 1616
P28_ST00131 1494
P28_SP00119 1536
P28_ST00132 1551 hydroxychloroquine, 0000000000000000000
P28_SP00120 1998
P28_ST00133 197 following
P28_TL00014 1680 1780
P28_ST00134 retroductal
P28_SP00121 686 1712
P28_ST00135 704 delivery
P28_SP00122 874 1721
P28_ST00136 to
P28_SP00123 929
P28_ST00137 945
P28_SP00124 967
P28_ST00138 984 129 single
P28_SP00125
P28_ST00139 1131 54 rat
P28_SP00126
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P28_ST00141 1543 127 gland.
P28_SP00128 1670
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P28_ST00144 1867 2006, 0.41 58870
P28_SP00131 1976 1719
P28_ST00145 235 12:137-144.
P28_TL00015 1786
P28_ST00146 36.
P28_SP00132 1818
P28_ST00147 195 O'Connell
P28_SP00133 647
P28_ST00148 666 BC,
P28_SP00134 734 1825
P28_ST00149 753
P28_SP00135 1827
P28_ST00150 896
P28_SP00136 935
P28_ST00151 954 317 Jacobson-Kram
P28_SP00137 1271
P28_ST00152 37 D,
P28_SP00138 1328
P28_ST00153 1349 113
P28_SP00139 1462
P28_ST00154 1482
P28_SP00140 1539
P28_ST00155 1560 250 Distribution
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P28_ST00156 1828
P28_SP00142 1904
P28_ST00157 1921 159 toxicity
P28_TL00016 1891 1759
P28_ST00158 187 resulting
P28_SP00143 640 1932
P28_ST00159 656 98 from
P28_SP00144 754 1923
P28_ST00160 772 225
P28_SP00145 997
P28_ST00161 1014 vector
P28_SP00146 1152
P28_ST00162 1164 administration
P28_SP00147 1475
P28_ST00163 1492 40
P28_SP00148 1532
P28_ST00164 1549 1899
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P28_SP00150 1716
P28_ST00166
P28_SP00151 1901
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P28_SP00152 2033
P28_ST00168
P28_SP00153 2087
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P28_TL00017 1997 854
P28_ST00170 rats.
P28_SP00154 542
P28_ST00171 23 J
P28_SP00155 585
P28_ST00172 599 85 2000
P28_SP00156 684
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P28_SP00158
P28_ST00175 2003, 0.39 58880
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P28_ST00176 1069 32:414-421.
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P28_SP00160 2134
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P28_SP00161 602 2143
P28_ST00179 622 H,
P28_SP00162 659 2141
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P28_SP00163
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P28_SP00164 961
P28_ST00182 982
P28_SP00165 1095
P28_ST00183 1115
P28_SP00166 1172
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P28_ST00185 1404 62 for
P28_SP00168 1466
P28_ST00186 1478
P28_SP00169 1544
P28_ST00187 193 systemic
P28_SP00170 1753
P28_ST00188 1770
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P28_SP00172
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P28_ST00191 217 transgene
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P28_SP00175
P28_ST00194
P28_SP00176 1149
P28_ST00195 1165 154 glands.
P28_SP00177 1319
P28_ST00196 1338 Hum
P28_SP00178 1433
P28_ST00197 1450 Gene
P28_SP00179 1557
P28_ST00198
P28_SP00180
P28_ST00199 1683 105 ^996, 0.37 87770
P28_SP00181 1788 2246
P28_ST00200 1807 7:2177-2184.
P28_TL00020 2313
P28_ST00201 38.
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P28_ST00205 858 38
P28_SP00186
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P28_ST00207 1140 F,
P28_SP00188
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P28_ST00209 1273 GG,
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P28_SP00191 1473
P28_ST00211
P28_SP00192 1531
P28_ST00212 Yeh
P28_SP00193 1626
P28_ST00213 CK,
P28_SP00194 1714
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P28_SP00195 1848
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P28_SP00196 1925
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P28_ST00241
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P28_SP00221 651 2775
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P16_SP00018 852
P16_ST00020 870 416
P16_SP00019 906
P16_ST00021 921
P16_SP00020 942
P16_ST00022 957
P16_SP00021 1034
P16_ST00023 1051
P16_SP00022 1088
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P16_SP00023 1293
P16_ST00025 1309 29 in
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P16_SP00025 1517
P16_ST00027 1531 35 to
P16_SP00026 1566
P16_ST00028 91
P16_SP00027 1675
P16_ST00029 1694 166
P16_SP00028 1860
P16_ST00030 1877
P16_SP00029 2092
P16_ST00031 2108
P16_SP00030 2144
P16_ST00032 2162 44
P16_TL00003 300 521 1920
P16_ST00033
P16_SP00031 377 553
P16_ST00034 394
P16_SP00032 431
P16_ST00035 445 529 82 age.
P16_SP00033 527 562
P16_ST00036 558 84 This
P16_SP00034 642
P16_ST00037 659 observation
P16_SP00035 890
P16_ST00038 909 109 might 00000
P16_SP00036 1018
P16_ST00039 46 be
P16_SP00037
P16_ST00040 1097 198 supported 0.98 000000100
P16_SP00038 1295
P16_ST00041 1314 by
P16_SP00039 1358
P16_ST00042 1373 61 the
P16_SP00040 1434
P16_ST00043 1451 206 differential 000000000000
P16_SP00041 1657
P16_ST00044 287 immunological 0000000000000
P16_SP00042 1963
P16_ST00045 1981 39 or
P16_SP00043 2020
P16_ST00046 2035 185 biological 0000000000
P16_TL00004 626 1682
P16_ST00047 634 183 response
P16_SP00044 486 667
P16_ST00048 503
P16_SP00045 541 658
P16_ST00049 555
P16_SP00046 647
P16_ST00050 664 627
P16_SP00047 699
P16_ST00051 715 163 different
P16_SP00048 878
P16_ST00052 893 95 ages
P16_SP00049
P16_ST00053 1005 71 and
P16_SP00050 1076
P16_ST00054 1093
P16_SP00051 1154
P16_ST00055 1171 effect
P16_SP00052 1280
P16_ST00056 1296
P16_SP00053 1333 12
P16_ST00057 1345
P16_SP00054 1560
P16_ST00058 1576 147 exerted 0000100
P16_SP00055 1723
P16_ST00059 1742 45 on
P16_SP00056 1787
P16_ST00060 1804
P16_SP00057 1865
P16_ST00061 1883 102 mice.
P16_TL00005 454 732
P16_ST00062 172 Previous
P16_SP00058 764
P16_ST00063 643 141 studies 0000000
P16_SP00059 784
P16_ST00064 802 94 have
P16_SP00060 896
P16_ST00065 914 177 indicated
P16_SP00061 1091
P16_ST00066 1108 75 that
P16_SP00062 1183
P16_ST00067 1199 740 121 genes
P16_SP00063 1320 773
P16_ST00068 1337 129 placed
P16_SP00064 1466
P16_ST00069 1482 114 within
P16_SP00065 1596
P16_ST00070 1612 79 Ad5
P16_SP00066 1691
P16_ST00071 1707 733 145 vectors
P16_SP00067 1852
P16_ST00072 1869 are
P16_SP00068 1930
P16_ST00073 1948 182 generally
P16_TL00006 302 837 1685
P16_ST00074 expressed
P16_SP00069 508
P16_ST00075 525 transiently
P16_SP00070 731
P16_ST00076 748
P16_SP00071 819 869
P16_ST00077 838 123 locally
P16_SP00072 961
P16_ST00078 978 restricted
P16_SP00073 1160
P16_ST00079 1179 (i.e.,
P16_SP00074 1261
P16_ST00080 88 7-14
P16_SP00075 1368
P16_ST00081 1385 107 days)
P16_SP00076 1492
P16_ST00082 1511 81 [29].
P16_SP00077 1592
P16_ST00083 1623 76 The
P16_SP00078 1699
P16_ST00084 1717 149 40 present
P16_SP00079 1866
P16_ST00085 1882 105 study
P16_TL00007 1944
P16_ST00086 274 demonstrates
P16_SP00080 576 974
P16_ST00087 591
P16_SP00081 666
P16_ST00088 682 950
P16_SP00082 703
P16_ST00089 721 rapid
P16_SP00083 816 983
P16_ST00090 834
P16_SP00084 905
P16_ST00091 924 201 significant
P16_SP00085 1125
P16_ST00092 1141 168 increase
P16_SP00086
P16_ST00093 1327
P16_SP00087 1356
P16_ST00094 1374 60
P16_SP00088
P16_ST00095 1452 levels
P16_SP00089 1564
P16_ST00096 1581
P16_SP00090 1619
P16_ST00097 1633 142 plasma
P16_SP00091 1775
P16_ST00098 1795 IL-17A
P16_SP00092 1924
P16_ST00099 1938 80 was
P16_SP00093 2018
P16_ST00100 2034 158 affected
P16_SP00094 2192
P16_ST00101 2210 943
P16_TL00008 305 1048 1799
P16_ST00102 42
P16_SP00095 347
P16_ST00103 366 93 days
P16_SP00096 459 1089
P16_ST00104 476 330 post-cannulation 0000000000000000
P16_SP00097 806
P16_ST00105 825
P16_SP00098
P16_ST00106 885
P16_SP00099 945
P16_ST00107 960
P16_SP00100 1175
P16_ST00108 1190 1049 transgene
P16_SP00101 1391
P16_ST00109 1407 132 vector.
P16_SP00102 1539
P16_ST00110 1573
P16_SP00103 1824
P16_ST00111 1843 68 this
P16_SP00104 1911
P16_ST00112 1928 176 systemic
P16_TL00009 1153 1914
P16_ST00113
P16_SP00105 471 1185
P16_ST00114 489
P16_SP00106 518
P16_ST00115 538 IL17
P16_SP00107 621
P16_ST00116 638 164 cytokine
P16_SP00108 1194
P16_ST00117 820 113
P16_SP00109 933
P16_ST00118 949 correlated
P16_SP00110 1147
P16_ST00119 1164 78 with
P16_SP00111 1242
P16_ST00120 1260
P16_SP00112 1461
P16_ST00121 1478 191 increases
P16_SP00113 1669
P16_ST00122 1686 30
P16_SP00114 1716
P16_ST00123 1734 splenic
P16_SP00115 1875
P16_ST00124 1891 130
P16_SP00116 2021
P16_ST00125 2037 180 secreting
P16_TL00010 1259 1923
P16_ST00126 143 CD4+T
P16_SP00117 1291
P16_ST00127 461 cells
P16_SP00118 549
P16_ST00128 565 74
P16_SP00119 639
P16_ST00129 656 179 persisted
P16_SP00120 835 1300
P16_ST00130 853
P16_SP00121 889
P16_ST00131 least
P16_SP00122 998
P16_ST00132 1017 43
P16_SP00123 1060
P16_ST00133
P16_SP00124
P16_ST00134 1168 53 for
P16_SP00125 1221
P16_ST00135 1236
P16_SP00126 1328
P16_ST00136 1344 138 treated
P16_SP00127
P16_ST00137 1501
P16_SP00128 1536
P16_ST00138 1552
P16_SP00129
P16_ST00139 1588
P16_SP00130 1665
P16_ST00140 1681
P16_SP00131 1719
P16_ST00141 1732 1267
P16_SP00132
P16_ST00142 1821
P16_SP00133 1892 22
P16_ST00143 1
P16_SP00134 1926
P16_ST00144 1939
P16_SP00135 1951
P16_ST00145 1972
P16_SP00136 2049
P16_ST00146 2065
P16_SP00137 2118
P16_ST00147 2133
P16_TL00011 1364 1880
P16_ST00148
P16_SP00138 1396
P16_ST00149 458 1365
P16_SP00139 493
P16_ST00150 512
P16_SP00140
P16_ST00151 570
P16_SP00141
P16_ST00152
P16_SP00142 701
P16_ST00153 1372
P16_SP00143 797 1405
P16_ST00154 828 124 These
P16_SP00144 952
P16_ST00155 969 256 observations
P16_SP00145 1225
P16_ST00156 1243
P16_SP00146 1420
P16_ST00157 1437
P16_SP00147
P16_ST00158 1526
P16_SP00148 1587
P16_ST00159 1602
P16_SP00149
P16_ST00160 1697 125 vector
P16_SP00150 1822
P16_ST00161 1836
P16_SP00151 1945
P16_ST00162 1959
P16_SP00152 2038
P16_ST00163 2056 longer
P16_TL00012 1469
P16_ST00164 85 than
P16_SP00153 386
P16_ST00165 404 228 anticipated.
P16_SP00154 632 1510
P16_ST00166 663 173 Whether
P16_SP00155 836
P16_ST00167 849 69
P16_SP00156 918
P16_ST00168 934 110
P16_SP00157 1044
P16_ST00169 108
P16_SP00158
P16_ST00170
P16_SP00159 1230
P16_ST00171 1248 due
P16_SP00160
P16_ST00172 1336 1470
P16_SP00161 1371
P16_ST00173 1388 1477 an
P16_SP00162 1433
P16_ST00174 1453 144 indirect
P16_SP00163 1597
P16_ST00175 208 secondary
P16_SP00164 1820
P16_ST00176
P16_SP00165 1946
P16_ST00177 1961
P16_SP00166 1999
P16_ST00178 2011
P16_SP00167 2071
P16_ST00179 2087 Ad5-
P16_TL00013 1575 1741
P16_ST00180
P16_SP00168 387 1607
P16_ST00181 403
P16_SP00169
P16_ST00182 543 28 is
P16_SP00170 571
P16_ST00183 588 189 unknown.
P16_SP00171 777
P16_ST00184 798 In
P16_SP00172 829
P16_ST00185 847 addition,
P16_SP00173 1014 1614
P16_ST00186 1032
P16_SP00174
P16_ST00187 1110
P16_SP00175 1286 1616
P16_ST00188 1302
P16_SP00176
P16_ST00189 1488
P16_SP00177
P16_ST00190 1537 IL17A
P16_SP00178 1651
P16_ST00191 207 production
P16_SP00179 1876
P16_ST00192 1896
P16_SP00180
P16_ST00193 1957 local
P16_TL00014 1680 1839
P16_ST00194
P16_SP00181 1712
P16_ST00195
P16_SP00182 546 11
P16_ST00196 557
P16_SP00183 772
P16_ST00197 790 197 presented
P16_SP00184 987 1721
P16_ST00198 1006
P16_SP00185 1035
P16_ST00199 1053
P16_SP00186 1121
P16_ST00200 1138
P16_SP00187
P16_ST00201
P16_SP00188 1289
P16_ST00202 1306 203 consistent
P16_SP00189 1509
P16_ST00203 1523
P16_SP00190 1601
P16_ST00204 1620 169 previous
P16_SP00191 1789
P16_ST00205 1805
P16_SP00192
P16_ST00206 1964
P16_SP00193 2008
P16_ST00207 2026 Bruce
P16_TL00015 1786 1823
P16_ST00208 Baum's 000010
P16_SP00194 451 1818
P16_ST00209 469 laboratory
P16_SP00195 1827
P16_ST00210 685 148 [35-38].
P16_SP00196 833
P16_ST00211 863 Adesanya
P16_SP00197 1064
P16_ST00212 1082 et
P16_SP00198 1117
P16_ST00213 1133 al.
P16_SP00199 1174
P16_ST00214 1195 [39]
P16_SP00200 1266
P16_ST00215 1284 has
P16_SP00201 1353
P16_ST00216 1370 demonstrated
P16_SP00202 1644
P16_ST00217 1662
P16_SP00203 1736
P16_ST00218 1752 acinar
P16_SP00204
P16_ST00219 1889
P16_SP00205 1977
P16_ST00220 1994 1794 can
P16_SP00206 2062
P16_ST00221 2081
P16_TL00016
P16_ST00222 punctured
P16_SP00207 500 1932
P16_ST00223 532
P16_SP00208
P16_ST00224 593 retrograde
P16_SP00209 799
P16_ST00225 817 151 salivary
P16_SP00210
P16_ST00226 985 106 gland
P16_SP00211
P16_ST00227 229 cannulation
P16_SP00212 1339
P16_ST00228
P16_SP00213 1392
P16_ST00229 1408 1899
P16_SP00214 1429
P16_ST00230 1446 certain
P16_SP00215 1578
P16_ST00231 1595
P16_SP00216 1720
P16_ST00232 156 dosage.
P16_SP00217 1890
P16_ST00233 1921
P16_SP00218 1997
P16_ST00234 2015 131 injured
P16_TL00017
P16_ST00235
P16_SP00219 426 2029
P16_ST00236 440 87
P16_SP00220
P16_ST00237 which
P16_SP00221
P16_ST00238 675
P16_SP00222 769
P16_ST00239 786 270 compromised
P16_SP00223 1056
P16_ST00240 1075 mucosal
P16_SP00224 1239
P16_ST00241 1258 barrier
P16_SP00225 1389
P16_ST00242 1404 155 integrity
P16_SP00226 1559
P16_ST00243 allow
P16_SP00227 1678
P16_ST00244 1692
P16_SP00228 1745
P16_ST00245 1760 leakage
P16_SP00229 1915
P16_ST00246 1933
P16_SP00230 1970
P16_ST00247 1983
P16_SP00231 2043
P16_ST00248 2059 1998
P16_TL00018 2102 1867
P16_ST00249 253 systemically.
P16_SP00232 2143
P16_ST00250 589 Further 0001000
P16_SP00233 734 2134
P16_ST00251
P16_SP00234
P16_ST00252 907
P16_SP00235
P16_ST00253 Kagami
P16_SP00236
P16_ST00254 1135 2103
P16_SP00237
P16_ST00255 1186
P16_SP00238 1228
P16_ST00256 [37]
P16_SP00239 1319
P16_ST00257
P16_SP00240
P16_ST00258 1428 52 He
P16_SP00241 1480
P16_ST00259 1497
P16_SP00242 1532
P16_ST00260
P16_SP00243 1589
P16_ST00261 1610 [40]
P16_SP00244
P16_ST00262 provided
P16_SP00245 1881
P16_ST00263 evidence
P16_SP00246 2078
P16_ST00264 2095
P16_TL00019 2207 1927
P16_ST00265 117 ductal
P16_SP00247 419 2239
P16_ST00266 437
P16_SP00248
P16_ST00267 684
P16_SP00249 722
P16_ST00268 735 152
P16_SP00250 887 2248
P16_ST00269 903 glands
P16_SP00251
P16_ST00270 2215
P16_SP00252 1119
P16_ST00271 also
P16_SP00253 1217
P16_ST00272
P16_SP00254 1329
P16_ST00273 1347
P16_SP00255
P16_ST00274 1538 effects
P16_SP00256
P16_ST00275
P16_SP00257 1758
P16_ST00276 1774 2208
P16_SP00258 1809
P16_ST00277 1825
P16_SP00259 1885
P16_ST00278 1902 secretory
P16_SP00260
P16_ST00279 2105 nature
P16_TL00020 2313
P16_ST00280
P16_SP00261 339 2345
P16_ST00281 352
P16_SP00262 412
P16_ST00282 429
P16_SP00263 581 2354
P16_ST00283 597
P16_SP00264 729
P16_ST00284 743
P16_SP00265 857
P16_ST00285 875 2321 62
P16_SP00266 937
P16_ST00286 well
P16_SP00267 1028
P16_ST00287 1046 endowed
P16_SP00268 1226
P16_ST00288
P16_SP00269 1321
P16_ST00289 1340 134 protein
P16_SP00270 1474
P16_ST00290 187 synthesis
P16_SP00271 1679
P16_ST00291 1696 organelles
P16_SP00272
P16_ST00292
P16_SP00273 1991
P16_ST00293 2009 2314
P16_TL00021 2418 1837
P16_ST00294 217 machinery.
P16_SP00274 520 2459 -53
P16_ST00295 467 2524 271 Nevertheless, 0.99 0000010000000
P16_SP00275 738 2563
P16_ST00296 757 these
P16_SP00276 865 2556
P16_ST00297 883
P16_SP00277 1139
P16_ST00298 1155 2532
P16_SP00278
P16_ST00299 1234 204
P16_SP00279 1438
P16_ST00300
P16_SP00280 1529
P16_ST00301 1547
P16_SP00281
P16_ST00302 1624 2525 concept
P16_SP00282 1782 2565
P16_ST00303 1796
P16_SP00283 1871
P16_ST00304 1886 57 SS
P16_SP00284 1943
P16_ST00305 1960 develops
P16_TL00022 2629 1864
P16_ST00306 along
P16_SP00285 409 2670
P16_ST00307 427 specific
P16_SP00286 578
P16_ST00308
P16_SP00287 778
P16_ST00309 2637 processes
P16_SP00288 1001
P16_ST00310 1019
P16_SP00289 2661
P16_ST00311 1066
P16_SP00290 1087
P16_ST00312 1105 sequential
P16_SP00291 1308
P16_ST00313 1325 fashion
P16_SP00292
P16_ST00314 1487
P16_SP00293 1558
P16_ST00315 1577 237 interference
P16_SP00294 1814
P16_ST00316 1829
P16_SP00295 1907
P16_ST00317
P16_SP00296 1992
P16_ST00318 2010 process
P16_TL00023 2734 1832
P16_ST00319 alters
P16_SP00297 410 2766
P16_ST00320 260 development
P16_SP00298 687 2775
P16_ST00321 702
P16_SP00299 739
P16_ST00322 753 disease
P16_SP00300
P16_ST00323 925 96 [1-3].
P16_SP00301 1021
P16_ST00324 1065 Therefore,
P16_SP00302 1271 2773
P16_ST00325 1290
P16_SP00303
P16_ST00326 1375
P16_SP00304
P16_ST00327 128 clearly
P16_SP00305 1625
P16_ST00328 1643 indicates
P16_SP00306 1819
P16_ST00329 1835
P16_SP00307 1895
P16_ST00330 1913 221 pathogenic
P16_TL00024 2840 1773
P16_ST00331 2841
P16_SP00308 2872
P16_ST00332
P16_SP00309 482
P16_ST00333 498
P16_SP00310
P16_ST00334 644
P16_SP00311 674
P16_ST00335 693 inducing
P16_SP00312 2881
P16_ST00336 SS-like
P16_SP00313 1016
P16_ST00337 232 phenotypes
P16_SP00314
P16_ST00338 when
P16_SP00315 1387
P16_ST00339 219 cannulated
P16_SP00316
P16_ST00340
P16_SP00317 1672
P16_ST00341 1690
P16_SP00318 1750
P16_ST00342 1767
P16_SP00319 1919
P16_ST00343 1935 glands.
P16_TB00002 1249 3047
P16_TL00025 1255 3053
P16_ST00344


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P22_ST00032
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P22_TL00004 302 784 1804
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P22_SP00045 637
P22_ST00049 656 104 Craig
P22_SP00046 760 825
P22_ST00050 779 Meyers
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P5_SP00031 810
P5_ST00035 853 42 At
P5_SP00032 895
P5_ST00036 910 107 times
P5_SP00033 1017
P5_ST00037 1034 indicated
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P5_ST00038 1230 30 in
P5_SP00035 1260
P5_ST00039 1277 60 the
P5_SP00036 1337
P5_ST00040 1353 81 text,
P5_SP00037 1434 823
P5_ST00041 1455
P5_SP00038 1546
P5_ST00042 1561
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P5_ST00045 1974 150 cervical
P5_TL00005 890 1805
P5_ST00046 dislocation
P5_SP00042 513
P5_ST00047 530 174 following
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P5_ST00048 722 98 deep
P5_SP00044 820
P5_ST00049 837 303 anesthetization
P5_SP00045
P5_ST00050 1156 78 with
P5_SP00046 1234
P5_ST00051 1253 204 39 isoflurane,
P5_SP00047 1457 929
P5_ST00052 1477 90 after
P5_SP00048 1567
P5_ST00053 1579 114 which
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P5_ST00055 1862
P5_SP00051 1959
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P5_TL00006 995 1844
P5_ST00057 193 explanted
P5_SP00052 495 1036
P5_ST00058 53 for
P5_SP00053 566 1027
P5_ST00059 187 analyses.
P5_SP00054 767 34
P5_ST00060 801 87 Both
P5_SP00055 888
P5_ST00061
P5_SP00056 965
P5_ST00062 983 172 breeding
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P5_ST00063 1174
P5_SP00058 1245
P5_ST00064 1264 1003 68 use
P5_SP00059 1332
P5_ST00065 1350 37 of
P5_SP00060 1387 13
P5_ST00066 1400 108 these
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P5_ST00067 1526
P5_SP00062 1680
P5_ST00068 1695 54
P5_SP00063 1749
P5_ST00069 1761 61
P5_SP00064
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P5_ST00071 2005 141 studies
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P5_ST00072 1109
P5_SP00066 397 1133
P5_ST00073 414 186 approved
P5_SP00067 600 1142
P5_ST00074 619
P5_SP00068 662
P5_ST00075 678
P5_SP00069 738
P5_ST00076 757 196 University
P5_SP00070 953
P5_ST00077 969
P5_SP00071 1007
P5_ST00078 1022 168 Florida's 0.99 000000010
P5_SP00072 1190
P5_ST00079 1208 137 lACUC 0.97
P5_SP00073 1345
P5_ST00080 1362
P5_SP00074 1433
P5_ST00081 1453 80 IBC.
P5_SP00075 1533
P5_ST00082 1566 159 Salivary
P5_SP00076 1725
P5_ST00083 1741 glands
P5_SP00077 1873
P5_ST00084 1889
P5_SP00078 1927
P5_ST00085 1941
P5_SP00079 2032
P5_ST00086 2048 96
P5_TL00008 1206 1948
P5_ST00087 cannulated
P5_SP00080 521 1238
P5_ST00088 537
P5_SP00081
P5_ST00089 634 1214 mouse
P5_SP00082 766
P5_ST00090 786 364 IL-17A-expressing 00000000000000000
P5_SP00083 1150 1247
P5_ST00091 1166 215 Ad5-IL17A
P5_SP00084 1381
P5_ST00092 1397 1207 124 vector
P5_SP00085 1521
P5_ST00093 1536 103 using
P5_SP00086 1639
P5_ST00094 206 retrograde
P5_SP00087 1864
P5_ST00095 1883 injections
P5_SP00088 2069
P5_ST00096 2085 36 at
P5_SP00089 2121
P5_ST00097 either
P5_TL00009 1311 1870
P5_ST00098 7
P5_SP00090 323 1343
P5_ST00099 338 128 weeks
P5_SP00091 466
P5_ST00100 484 (wks)
P5_SP00092 587 1352
P5_ST00101 605
P5_SP00093 643
P5_ST00102 656 1319 72 age
P5_SP00094 728
P5_ST00103 746 (n 11)
P5_SP00095 874
P5_ST00104 892 or
P5_SP00096
P5_ST00105 948 44
P5_SP00097 992
P5_ST00106 77 wks
P5_SP00098 1084
P5_ST00107
P5_SP00099 1138
P5_ST00108 1152
P5_SP00100 1223
P5_ST00109 1242 8).
P5_SP00101 1355
P5_ST00110 1389 In
P5_SP00102 1420
P5_ST00111 1438 167 addition,
P5_SP00103 1605
P5_ST00112 1625 92
P5_SP00104 1717
P5_ST00113 1734 1312 35
P5_SP00105 1769
P5_ST00114 1784 22 6
P5_SP00106 1806
P5_ST00115 1821
P5_SP00107 1898
P5_ST00116 1916 102 4)
P5_SP00108 2018
P5_ST00117 2036
P5_SP00109 2107
P5_ST00118 2128
P5_TL00010 1417 1933
P5_ST00119
P5_SP00110 1449
P5_ST00120
P5_SP00111 497 1458
P5_ST00121 1425
P5_SP00112 610
P5_ST00122 628 183 randomly
P5_SP00113 811
P5_ST00123 828 165 selected
P5_SP00114 993
P5_ST00124 1011
P5_SP00115 1082
P5_ST00125 1102 93 used
P5_SP00116 1195
P5_ST00126 1213 as
P5_SP00117 1257
P5_ST00127 1275 pre-treated
P5_SP00118 1493
P5_ST00128 1511
P5_SP00119 1550
P5_ST00129 1565 166 baseline
P5_SP00120 1731
P5_ST00130 1748 analysis.
P5_SP00121 1920
P5_ST00131 1950 94 Age-
P5_SP00122 2044
P5_ST00132 2061
P5_SP00123 2132
P5_ST00133 2150 83 sex-
P5_TL00011 1522 1854
P5_ST00134 matched
P5_SP00124 472 1554
P5_ST00135 491 control
P5_SP00125 623
P5_ST00136 641
P5_SP00126 836
P5_ST00137 856
P5_SP00127 947
P5_ST00138 10
P5_SP00128 1079
P5_ST00139 1097 1530 64 per
P5_SP00129 1161
P5_ST00140 1175
P5_SP00130
P5_ST00141 127 group)
P5_SP00131 1391
P5_ST00142 1410 received
P5_SP00132
P5_ST00143 1594
P5_SP00133 1654
P5_ST00144 1670 Ad5-LacZ
P5_SP00134 1866
P5_ST00145
P5_SP00135 2015
P5_ST00146 1523 125
P5_TL00012 1628 515
P5_ST00147
P5_SP00136 406 1669
P5_ST00148 423
P5_SP00137 1660
P5_ST00149 501 1636 same
P5_SP00138
P5_ST00150 627 191 protocols.
P5_TL00013 1733 1026
P5_ST00151 239 Production 0100000000
P5_SP00139 541 1765
P5_ST00152 558 45
P5_SP00140 603 9
P5_ST00153 612 208
P5_SP00141
P5_ST00154 834 82
P5_SP00142 916 11
P5_ST00155 927
P5_SP00143
P5_ST00156 1170 158 vectors 0.90 0500010
P5_TL00014 1838 1915
P5_ST00157
P5_SP00144 376
P5_ST00158 248 recombinant
P5_SP00145
P5_ST00159 659 220 adenovirus
P5_SP00146 879
P5_ST00160 1839 144
P5_SP00147 1039
P5_ST00161 1057
P5_SP00148
P5_ST00162 1169 29
P5_SP00149 1198
P5_ST00163 1216 this
P5_SP00150 1284
P5_ST00164 1301 105 study
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P5_ST00165 1421
P5_SP00152 1518
P5_ST00166 1535 generously
P5_SP00153 1755
P5_ST00167 1773
P5_SP00154 1942
P5_ST00168
P5_SP00155
P5_ST00169 2024 52 Dr.
P5_SP00156 2076
P5_ST00170 2095 Jay
P5_SP00157 2163
P5_ST00171 2182 K.
P5_TL00015 1944 1876
P5_ST00172 Kolls
P5_SP00158 1976
P5_ST00173 415 213 (Children's
P5_SP00159 1985
P5_ST00174 646 Hospital
P5_SP00160 805
P5_ST00175
P5_SP00161 860
P5_ST00176 876 210 Pittsburgh,
P5_SP00162 1086
P5_ST00177 1108
P5_SP00163 1318
P5_ST00178 1339 PA).
P5_SP00164
P5_ST00179 1451 These
P5_SP00165 1575
P5_ST00180 1591 1945 145
P5_SP00166 1736
P5_ST00181 1753 1952 are
P5_SP00167 1814
P5_ST00182 1833 118 based
P5_SP00168 1951
P5_ST00183 1969
P5_SP00169
P5_ST00184
P5_SP00170 2092
P5_ST00185 2108 first
P5_TL00016 2049 1908
P5_ST00186 generation
P5_SP00171 2090
P5_ST00187 531 221
P5_SP00172 752 2081
P5_ST00188 768 2050 serotype
P5_SP00173 940
P5_ST00189 957
P5_SP00174 978
P5_ST00190 106 (Ad5)
P5_SP00175
P5_ST00191 1120
P5_SP00176 1191
P5_ST00192 1209 shown
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P5_ST00193 to
P5_SP00178 1388
P5_ST00194 160 produce
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P5_SP00180 1671
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P5_ST00199
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P5_ST00200 454 48 IL-
P5_SP00184 502
P5_ST00201 522 17A
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P5_ST00202 613
P5_SP00186 684
P5_ST00203 LacZ
P5_SP00187 800
P5_ST00204 818 171 products
P5_SP00188 989 2196
P5_ST00205 1006 148 [22-24].
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P5_ST00206 1172 To
P5_SP00190
P5_ST00207 1240 119 obtain
P5_SP00191 1359
P5_ST00208 1377 178 sufficient
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P5_ST00211 1827
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P5_SP00196 1954
P5_ST00213 1972
P5_TL00018 2260 1931
P5_ST00214 studies,
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P5_ST00215 473 each
P5_SP00198 567 2292
P5_ST00216 586
P5_SP00199
P5_ST00217 849 2261
P5_SP00200 973
P5_ST00218 985 2268 was
P5_SP00201 1065
P5_ST00219 amplified
P5_SP00202 2301
P5_ST00220 1279
P5_SP00203 1308
P5_ST00221 1328 164 HEK293
P5_SP00204 1492
P5_ST00222 1510 cells,
P5_SP00205 1607
P5_ST00223 purified
P5_SP00206 1772
P5_ST00224 1791
P5_SP00207 1834
P5_ST00225 1850 two
P5_SP00208 1918
P5_ST00226 1936 135 rounds
P5_SP00209 2071
P5_ST00227 2088
P5_SP00210 2126
P5_ST00228 2139 CsCI 0.96
P5_TL00019 2365
P5_ST00229 gradient
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P5_ST00230 480 282 centrifugation,
P5_SP00212 762
P5_ST00231 780 then
P5_SP00213 865 2397
P5_ST00232 883 dialyzed
P5_SP00214 1046
P5_ST00233 1064 against
P5_SP00215
P5_ST00234 1227 69 100
P5_SP00216 1296
P5_ST00235 1314 70 mM
P5_SP00217 1384
P5_ST00236 1402 Tris-HCI
P5_SP00218
P5_ST00237 1584 67 (pH
P5_SP00219 1651
P5_ST00238 7.4),
P5_SP00220
P5_ST00239 1777
P5_SP00221
P5_ST00240
P5_SP00222
P5_ST00241 1928 MgCb 0.78 0008
P5_SP00223 2046
P5_ST00242 2063
P5_SP00224 2134
P5_ST00243 10%
P5_TL00020 2471 861
P5_ST00244 (vv) 0.91 00400
P5_SP00225 386 2512
P5_ST00245 404 glycerol,
P5_SP00226 568
P5_ST00246 2479
P5_SP00227 632 2503
P5_ST00247 648 194 described
P5_SP00228 842
P5_ST00248 elsewhere
P5_SP00229
P5_ST00249 1083 [25].
P5_TL00021 2576 1582
P5_ST00250 242 Retrograde 0501001005
P5_SP00230 544 2617
P5_ST00251 salivary
P5_SP00231 730
P5_ST00252 742 123 gland
P5_SP00232
P5_ST00253 253 cannulation
P5_SP00233 1132 2608
P5_ST00254 1149
P5_SP00234 1194
P5_ST00255 1203
P5_SP00235 1411
P5_ST00256 1426 2584 0.63
P5_SP00236 1474
P5_ST00257 1483 222 0.74 172150211
P5_SP00237 1705
P5_ST00258 2577 0730700
P5_TL00022 2682 1882
P5_ST00259 Previous
P5_SP00238 476 2714
P5_ST00260 493
P5_SP00239
P5_ST00261 652 have
P5_SP00240
P5_ST00262 763 275 demonstrated 000000000000
P5_SP00241 1038
P5_ST00263 1055 that
P5_SP00242 1130
P5_ST00264 207
P5_SP00243 2723
P5_ST00265 1370
P5_SP00244
P5_ST00266 1538
P5_SP00245 1645
P5_ST00267 1663 229
P5_SP00246 1892
P5_ST00268 1911 28 is
P5_SP00247 1939
P5_ST00269 1956 2690 an
P5_SP00248 2002
P5_ST00270 2020 effective
P5_TL00023 2787 1722
P5_ST00271 146 method
P5_SP00249 449 2819
P5_ST00272 467 2788
P5_SP00250
P5_ST00273 519 109 direct
P5_SP00251
P5_ST00274 644 89 local
P5_SP00252 733
P5_ST00275 750 2795 gene
P5_SP00253 848 2828
P5_ST00276 216 expression
P5_SP00254 1081
P5_ST00277
P5_SP00255
P5_ST00278 1147
P5_SP00256
P5_ST00279 1225
P5_SP00257 1376
P5_ST00280 1393 131
P5_SP00258 1524
P5_ST00281 1541 [26-28].
P5_SP00259 1689
P5_ST00282 1723
P5_SP00260 1754
P5_ST00283 brief,
P5_SP00261 1867 2826
P5_ST00284 1888 prior
P5_SP00262 1977
P5_ST00285 1990
P5_TL00024 2892
P5_ST00286 240 cannulation,
P5_SP00263 542 2931
P5_ST00287 562
P5_SP00264 2924
P5_ST00288 675 2900
P5_SP00265
P5_ST00289 822
P5_SP00266 902
P5_ST00290 919 254 anesthetized
P5_SP00267 1173
P5_ST00291 1189
P5_SP00268 1267
P5_ST00292 1285
P5_SP00269
P5_ST00293 ketamine:xylazine
P5_SP00270 1684 2933
P5_ST00294 1702 mixture
P5_SP00271
P5_ST00295 86 (100
P5_SP00272
P5_ST00296 mgmL, 004000
P5_SP00273 2114 23
P5_ST00297 2137 1
P5_TL00025 1265 3053
P5_ST00298


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P14_ST00012 1861 129 IL-17A
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P14_ST00025 1456 102 mice 0.87 0005
P14_SP00023 1558
P14_ST00026 1573 199 following
P14_SP00024 1772
P14_ST00027 1788 253 cannulation
P14_SP00025 2041
P14_ST00028 2058 87 with 0000
P14_TL00004 301 732 381
P14_ST00029 62 Ad 0.95 01
P14_SP00026 363 764 1
P14_ST00030 364 52 5-1
P14_SP00027 416
P14_ST00031 417 48 LI
P14_SP00028 465 7
P14_ST00032 472 23
P14_SP00029 495
P14_ST00033 29 A
P14_SP00030 524
P14_ST00034 543 733 139 vector 0.92 030010
P14_TL00005 837
P14_ST00035 50 To
P14_SP00031 869
P14_ST00036 368 200 determine
P14_SP00032 568
P14_ST00037 586 if
P14_SP00033 607
P14_ST00038 619 61
P14_SP00034 680
P14_ST00039 697 expression
P14_SP00035 913 878
P14_ST00040 931 38
P14_SP00036 969 13
P14_ST00041 982 845 221 33 exogenous
P14_SP00037 1203
P14_ST00042 1221 130
P14_SP00038 1351
P14_ST00043 1367 68 can
P14_SP00039 1435
P14_ST00044 1455 induce
P14_SP00040 1584
P14_ST00045 1601 152
P14_SP00041 1753
P14_ST00046 1770 106
P14_SP00042 1876
P14_ST00047 1894 238 dysfunction, 000000000000
P14_TL00006 942
P14_ST00048 113 saliva
P14_SP00043 974
P14_ST00049 431 168 volumes
P14_SP00044 599
P14_ST00050 614 54 for
P14_SP00045 668
P14_ST00051 682 93 each
P14_SP00046 775
P14_ST00052 795 950 132 mouse
P14_SP00047 927
P14_ST00053 97 were
P14_SP00048 1039
P14_ST00054 1057 198 measured
P14_SP00049 1255
P14_ST00055 1273 943 at
P14_SP00050 1308
P14_ST00056 1327
P14_SP00051 1339
P14_ST00057 1360 55 wk
P14_SP00052 1415
P14_ST00058 1432 89 prior
P14_SP00053 1521 983
P14_ST00059 1534
P14_SP00054 1569
P14_ST00060 1585 201 treatment,
P14_SP00055 1786 981
P14_ST00061 1804 85 then
P14_SP00056 1889
P14_ST00062 1907 36
P14_SP00057 1943
P14_ST00063 1958 3-5
P14_SP00058 2020
P14_ST00064 2035
P14_TL00007 1048 1873
P14_ST00065 166 intervals
P14_SP00059 469 1080
P14_ST00066 486 post-cannulation. 00000000000000000
P14_SP00060 828 1089
P14_ST00067 860 195 0.93 00000400
P14_SP00061 1055
P14_ST00068 1075 91
P14_SP00062 1166
P14_ST00069 1183 74 that
P14_SP00063 1257
P14_ST00070 1274 167 received
P14_SP00064 1441
P14_ST00071 1459 control
P14_SP00065 1591
P14_ST00072 1607 197 Ad5-LacZ
P14_SP00066
P14_ST00073 1819 1049 125
P14_SP00067 1944
P14_ST00074
P14_SP00068 1993
P14_ST00075 2009
P14_SP00069 2030
P14_ST00076 2045 77 wks
P14_SP00070 2122
P14_ST00077 2139
P14_TL00008 1153 1893
P14_ST00078 1161 72 age
P14_SP00071 374 1194
P14_ST00079 391 exhibited
P14_SP00072 569 1185
P14_ST00080 587 118 stable
P14_SP00073 705
P14_ST00081 722 stimulated
P14_SP00074 926
P14_ST00082 944
P14_SP00075
P14_ST00083 1073
P14_SP00076 1241
P14_ST00084 1154
P14_SP00077 1293
P14_ST00085
P14_SP00078 1329
P14_ST00086 1345
P14_SP00079 1422
P14_ST00087 1439 83 post
P14_SP00080 1522
P14_ST00088 1537 191 treatment
P14_SP00081 1728 27
P14_ST00089 1755 78
P14_SP00082 1833
P14_ST00090 1851
P14_SP00083 1872
P14_ST00091 218 statistically 0000000000000
P14_SP00084 2107
P14_ST00092 2125 70 non SUBS_TYPE HypPart1 SUBS_CONTENT nonsignificant
P14_TL00009 1259 1901
P14_ST00093 significant HypPart2
P14_SP00085 503 1300
P14_ST00094 520 increase
P14_SP00086 1291
P14_ST00095 706
P14_SP00087 735
P14_ST00096 753
P14_SP00088 866
P14_ST00097 882
P14_SP00089 1050
P14_ST00098 1066 1260
P14_SP00090 1102
P14_ST00099 1120
P14_SP00091 1132
P14_ST00100 1146
P14_SP00092 1158
P14_ST00101 1179
P14_SP00093 1256
P14_ST00102
P14_SP00094 1357
P14_ST00103 1371 treatment.
P14_SP00095 1572 34
P14_ST00104 1606 271 39 Nevertheless, 0000010000000
P14_SP00096 1877 1298
P14_ST00105 1897
P14_SP00097 2092
P14_ST00106 2112
P14_TL00010 300 1364 1892
P14_ST00107 whose
P14_SP00098 430 1396
P14_ST00108
P14_SP00099 1405
P14_ST00109 615 glands
P14_SP00100 747
P14_ST00110 761 1372
P14_SP00101 858
P14_ST00111 875 219 cannulated
P14_SP00102 1094
P14_ST00112 1112 1365
P14_SP00103 1148
P14_ST00113 1163
P14_SP00104 1184
P14_ST00114 1199
P14_SP00105 1276
P14_ST00115
P14_SP00106 1331
P14_ST00116 1344
P14_SP00107 1416
P14_ST00117 1431
P14_SP00108 1509
P14_ST00118 1525 Ad5-IL17A
P14_SP00109 1741
P14_ST00119 1757
P14_SP00110 1935
P14_ST00120 1953
P14_SP00111 1974
P14_ST00121 1991
P14_TL00011 1469
P14_ST00122 71 and
P14_SP00112 373 1501
P14_ST00123 392 relatively
P14_SP00113 1510
P14_ST00124 95 rapid
P14_SP00114 681
P14_ST00125 699 185 decrease
P14_SP00115 884
P14_ST00126 902
P14_SP00116
P14_ST00127 949
P14_SP00117
P14_ST00128 1171
P14_SP00118 1284
P14_ST00129
P14_SP00119 1467
P14_ST00130 1483 75
P14_SP00120
P14_ST00131 1571 1477 80 was
P14_SP00121 1651
P14_ST00132 1669 1470 most
P14_SP00122 1764
P14_ST00133 1781 235 pronounced
P14_SP00123 2016
P14_ST00134
P14_SP00124 2070
P14_ST00135 2085
P14_SP00125 2106
P14_ST00136
P14_TL00012 1575
P14_ST00137 1576
P14_SP00126 386 1616
P14_ST00138 400
P14_SP00127 601 1614
P14_ST00139 620
P14_SP00128 691
P14_ST00140 709 this
P14_SP00129 777
P14_ST00141 794 231 observation
P14_SP00130 1025
P14_ST00142 1044 is
P14_SP00131
P14_ST00143 1583 94 seen
P14_SP00132
P14_ST00144 1201 even
P14_SP00133 1295
P14_ST00145 1314 22
P14_SP00134 1336
P14_ST00146 1348
P14_SP00135 1408
P14_ST00147 1426 112
P14_SP00136 1538
P14_ST00148 1554
P14_SP00137 1722
P14_ST00149 1739 are
P14_SP00138 1801
P14_ST00150 1818 196 converted 000000100
P14_SP00139 2014
P14_ST00151 2031
P14_SP00140 2066
P14_ST00152 2083
P14_TL00013 1680 1947
P14_ST00153 flow
P14_SP00141 1712
P14_ST00154 397 1681 rates
P14_SP00142 494
P14_ST00155 512 based
P14_SP00143 630
P14_ST00156 649 1688
P14_SP00144 694
P14_ST00157 710 154 weights
P14_SP00145 864 1721
P14_ST00158 881
P14_SP00146 918
P14_ST00159
P14_SP00147 991
P14_ST00160 1009 mice.
P14_SP00148 1111 30
P14_ST00161 1141 98 After
P14_SP00149 1239
P14_ST00162 1253
P14_SP00150
P14_ST00163 1289
P14_SP00151 1366
P14_ST00164 1384 82
P14_SP00152 1466
P14_ST00165 1481
P14_SP00153 1682 1719
P14_ST00166 1700 108 these
P14_SP00154
P14_ST00167 1827
P14_SP00155 1918
P14_ST00168 153 showed
P14_SP00156 2088
P14_ST00169
P14_SP00157 2127
P14_ST00170 2144 104 slight
P14_TL00014 1860
P14_ST00171 1794 recovery
P14_SP00158 474
P14_ST00172 492 149 (Figure
P14_SP00159 641
P14_ST00173 5A).
P14_SP00160 738 58
P14_ST00174 796 Similar
P14_SP00161 935
P14_ST00175 results
P14_SP00162
P14_ST00176 1095
P14_SP00163 1192
P14_ST00177 1209 183 observed
P14_SP00164 1392
P14_ST00178
P14_SP00165 1486
P14_ST00179 1504
P14_SP00166
P14_ST00180 1720
P14_SP00167 1811
P14_ST00181 1828
P14_SP00168 2047
P14_ST00182 2065 1787
P14_SP00169 2101
P14_ST00183 2119 44
P14_TL00015 1891 1863
P14_ST00184
P14_SP00170 377 1923
P14_ST00185 394
P14_SP00171
P14_ST00186 445 1899
P14_SP00172 517 1932
P14_ST00187 532
P14_SP00173 610
P14_ST00188
P14_SP00174 823
P14_ST00189 840
P14_SP00175 911
P14_ST00190 215
P14_SP00176 1142
P14_ST00191 1157 155 vectors;
P14_SP00177 1312 1930
P14_ST00192 however,
P14_SP00178 1523
P14_ST00193 1544 no
P14_SP00179 1589
P14_ST00194
P14_SP00180
P14_ST00195 1735 145 volume
P14_SP00181 1880
P14_ST00196 1898
P14_SP00182
P14_ST00197
P14_TL00016 1997 1931
P14_ST00198
P14_SP00183 485 2029
P14_ST00199 1998
P14_SP00184 539
P14_ST00200 553 time
P14_SP00185 636
P14_ST00201 654
P14_SP00186
P14_ST00202 704 268 euthanization
P14_SP00187 972
P14_ST00203 81 (i.e.,
P14_SP00188 1072 2038
P14_ST00204
P14_SP00189 1107
P14_ST00205
P14_SP00190
P14_ST00206
P14_SP00191 1230
P14_ST00207 1248 305 post-treatment) 000000000000000
P14_SP00192 1553
P14_ST00208 150
P14_SP00193
P14_ST00209 1738 5B).
P14_SP00194
P14_ST00210 1850 173 Whether
P14_SP00195 2023
P14_ST00211 2037 2005
P14_SP00196
P14_ST00212 2076 157 reversal
P14_TL00017 2102
P14_ST00213
P14_SP00197 339 2134
P14_ST00214 352
P14_SP00198 420
P14_ST00215 438 174 inhibition
P14_SP00199 612
P14_ST00216 629 116 would
P14_SP00200 745
P14_ST00217 763 2110 111 occur
P14_SP00201 874
P14_ST00218 889
P14_SP00202
P14_ST00219 109
P14_SP00203
P14_ST00220 1061 101 older
P14_SP00204 1162
P14_ST00221 1176 animals
P14_SP00205 1330
P14_ST00222 will
P14_SP00206
P14_ST00223 1424 137 require
P14_SP00207 1561 2143
P14_ST00224 1577 further 0001000
P14_SP00208 1709
P14_ST00225 1724 151 studies.
P14_SP00209 1875
P14_ST00226 1906 Thus,
P14_SP00210 2015 2141
P14_ST00227 2034
P14_TL00018 2207 1835
P14_ST00228 205 secretions
P14_SP00211 507 2239
P14_ST00229
P14_SP00212 561
P14_ST00230 576
P14_SP00213
P14_ST00231 685 177 receiving
P14_SP00214 862 2248
P14_ST00232 879
P14_SP00215 940
P14_ST00233 955
P14_SP00216 1170
P14_ST00234 2208
P14_SP00217 1310
P14_ST00235 1322 2215 96
P14_SP00218 1418
P14_ST00236 1436 233 significantly
P14_SP00219
P14_ST00237 1685 209 decreased
P14_SP00220
P14_ST00238 1915 1-2
P14_SP00221 1973
P14_ST00239 1992 months
P14_TL00019 2313 1694
P14_ST00240 2314 292 post-treatment 00000000000000
P14_SP00222 595 2354
P14_ST00241 608 when
P14_SP00223 714 2345
P14_ST00242 compared
P14_SP00224
P14_ST00243 948
P14_SP00225
P14_ST00244 1000
P14_SP00226 1205
P14_ST00245 1222
P14_SP00227
P14_ST00246
P14_SP00228
P14_ST00247 1383
P14_SP00229 1560
P14_ST00248
P14_SP00230 1638
P14_ST00249 1653
P14_SP00231
P14_ST00250 1865 vector.
P14_TB00002 1249 3047 42
P14_TL00020 3053
P14_ST00251


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SP P13_SP00001 480 342 18
P13_ST00002 498 147 smaller 0000000
P13_SP00002 645
P13_ST00003 658 67 foci 0000
P13_SP00003 725
P13_ST00004 743 203 containing 0000000000
P13_SP00004 946 351 17
P13_ST00005 963 112 fewer 00000
P13_SP00005 1075 16
P13_ST00006 1091 98 IL-17
P13_SP00006 1189
P13_ST00007 1207 150 positive 00000000
P13_SP00007 1357
P13_ST00008 1375 87 cells
P13_SP00008 1462
P13_ST00009 1479 198 compared
P13_SP00009 1677
P13_ST00010 1695 311 34 31 to 00
P13_SP00010 1729 19
P13_ST00011 1748 91 mice
P13_SP00011 1839
P13_ST00012 1857 177 receiving
P13_SP00012 2034
P13_ST00013 2051 61 the 000
P13_TL00002 301 415 1931
P13_ST00014 416 125 vector 000000
P13_SP00013 426 447 14
P13_ST00015 440 35 at
P13_SP00014 475
P13_ST00016 494 43
P13_SP00015 537 15
P13_ST00017 552 77 wks
P13_SP00016 629
P13_ST00018 646 37 of
P13_SP00017 683
P13_ST00019 697 423 72 33 age
P13_SP00018 769 456
P13_ST00020 787 (Figure
P13_SP00019 937
P13_ST00021 954 21 3
P13_SP00020 975
P13_ST00022 992 C-F
P13_SP00021 1064
P13_ST00023 1081 30 &
P13_SP00022 1111
P13_ST00024 1128 l-L).
P13_SP00023 1205
P13_ST00025 1237 214 Consistent 0.99
P13_SP00024 1451
P13_ST00026 1464 78 with
P13_SP00025 1542
P13_ST00027 1561 169 previous
P13_SP00026 1730
P13_ST00028 1746 243 39 observation, 000000000000
P13_SP00027 1989 454
P13_ST00029 2008 60
P13_SP00028 2068
P13_ST00030 2085
P13_TL00003 521 1847
P13_ST00031
P13_SP00029 368 553
P13_ST00032 387 29 in
P13_SP00030
P13_ST00033 435 92
P13_SP00031 527
P13_ST00034 543 138 treated
P13_SP00032 681
P13_ST00035 699 522 36
P13_SP00033 735
P13_ST00036 750 7
P13_SP00034 771
P13_ST00037
P13_SP00035 864
P13_ST00038 880 38
P13_SP00036 918
P13_ST00039 931 529
P13_SP00037 1003 562
P13_ST00040 1021 82 may
P13_SP00038 1103
P13_ST00041 1121 94 have
P13_SP00039 1215
P13_ST00042 1233 156 resulted
P13_SP00040 1389
P13_ST00043 1407 from
P13_SP00041 1494
P13_ST00044 1511
P13_SP00042 1571
P13_ST00045 1590 longer
P13_SP00043 1715
P13_ST00046 160 duration
P13_SP00044 1889
P13_ST00047 1907
P13_SP00045 1945 12
P13_ST00048 1957 83 time
P13_SP00046 2040
P13_ST00049 2058 90 after
P13_TL00004 626 1895
P13_ST00050 229 cannulation 00000000000
P13_SP00047 531
P13_ST00051 550 (19
P13_SP00048 611 667
P13_ST00052 wks)
P13_SP00049 717
P13_ST00053 736 180 reflecting
P13_SP00050 916
P13_ST00054 933
P13_SP00051 993
P13_ST00055 1010 208 decreases
P13_SP00052 1218
P13_ST00056 1235
P13_SP00053 1265 20
P13_ST00057 1285 129 IL-17A
P13_SP00054 1414
P13_ST00058 1431 634 122 24 serum
P13_SP00055 1553
P13_ST00059 1572 levels
P13_SP00056 1684
P13_ST00060 1701 71 and
P13_SP00057 1772
P13_ST00061 1805 144 IL-17A-
P13_SP00058 1949
P13_ST00062 1967
P13_SP00059 2117
P13_ST00063 2134 63 cell
P13_TL00005 303 732 1906
P13_ST00064 183 numbers.
P13_SP00060 486 764
P13_ST00065 Detailed
P13_SP00061
P13_ST00066 242 examination
P13_SP00062 941
P13_ST00067 959
P13_SP00063 997
P13_ST00068 1012 300 IL-17A-positive 000000000000000
P13_SP00064 1312 773
P13_ST00069 1329 88
P13_SP00065 1417
P13_ST00070 1434 170 revealed
P13_SP00066 1604
P13_ST00071 1621 74 that
P13_SP00067
P13_ST00072 1711 740 a
P13_SP00068 1732
P13_ST00073 1750 majority
P13_SP00069
P13_ST00074 1922
P13_SP00070 1960
P13_ST00075 1975 130
P13_SP00071 2105
P13_ST00076 2121
P13_TL00006 837 1820
P13_ST00077 845 62 are
P13_SP00072 364 869
P13_ST00078 382 838 149 40 present
P13_SP00073 878
P13_ST00079 548
P13_SP00074 577
P13_ST00080 594
P13_SP00075 654
P13_ST00081 673 47 LF
P13_SP00076 720
P13_ST00082 738
P13_SP00077 809
P13_ST00083 827 117 ductal
P13_SP00078 944
P13_ST00084 962
P13_SP00079 1050
P13_ST00085
P13_SP00080 1142
P13_ST00086 1160
P13_SP00081 1307
P13_ST00087 1322 224 percentage
P13_SP00082 1546
P13_ST00088 1563
P13_SP00083 1601
P13_ST00089 1615
P13_SP00084 1765
P13_ST00090 1782
P13_SP00085 1870
P13_ST00091 1886 110 found
P13_SP00086 1996
P13_ST00092 2015
P13_SP00087 2044
P13_ST00093 2061
P13_TL00007 942 1877
P13_ST00094 204 epithelium
P13_SP00088 506 983
P13_ST00095 524
P13_SP00089 595 974
P13_ST00096 613 123 acinar
P13_SP00090
P13_ST00097 cells.
P13_SP00091 848
P13_ST00098 882 272 Nevertheless, 0000000000000
P13_SP00092 1154 981
P13_ST00099 1172 109 these
P13_SP00093 1281
P13_ST00100 1298 85 data
P13_SP00094 1383
P13_ST00101 1400 943 support 0.98 0000001
P13_SP00095 1550
P13_ST00102 1565
P13_SP00096 1625
P13_ST00103 1642 158 concept
P13_SP00097 1800
P13_ST00104 1814 75
P13_SP00098
P13_ST00105 1903 187 formation
P13_SP00099 2090
P13_ST00106 2108
P13_TL00008 1048 1834
P13_ST00107 257 maintenance
P13_SP00100 560 1080
P13_ST00108
P13_SP00101 615
P13_ST00109 630
P13_SP00102 677
P13_ST00110 694 1056
P13_SP00103 756
P13_ST00111 774 due,
P13_SP00104 856 1087
P13_ST00112 876
P13_SP00105 906
P13_ST00113 925 1049 84 part, 0.97 00010
P13_SP00106 1009 1089
P13_ST00114 1027
P13_SP00107 1062
P13_ST00115 1078
P13_SP00108 1139
P13_ST00116 1156 216 expression
P13_SP00109 1372
P13_ST00117 1391
P13_SP00110 1503
P13_ST00118 1520
P13_SP00111 1558
P13_ST00119 1573 114 IL17A
P13_SP00112 1687
P13_ST00120 1704
P13_SP00113 1734
P13_ST00121 1751
P13_SP00114 1811
P13_ST00122 1828 152 salivary
P13_SP00115 1980
P13_ST00123 141 glands.
P13_TL00009 1259 1535
P13_ST00124 189 Changes
P13_SP00116 491 1300
P13_ST00125 509
P13_SP00117 1291
P13_ST00126 97 ANA
P13_SP00118 657
P13_ST00127 675 profiles
P13_SP00119 835
P13_ST00128 850 197 following
P13_SP00120 1047
P13_ST00129 1067 222 instillation
P13_SP00121 1289
P13_ST00130 1308 42
P13_SP00122 1350
P13_ST00131 1362 66
P13_SP00123 1428
P13_ST00132 1443 240 Ad5-IL-17A
P13_SP00124 1683
P13_ST00133 1699
P13_TL00010 1364 1864
P13_ST00134 With
P13_SP00125 388 1396
P13_ST00135 405
P13_SP00126 466
P13_ST00136 483 238 appearance
P13_SP00127 721 1405
P13_ST00137
P13_SP00128 775
P13_ST00138 791 B
P13_SP00129 815
P13_ST00139 832
P13_SP00130 903
P13_ST00140 920 26 T
P13_SP00131
P13_ST00141 250 lymphocytes
P13_SP00132 1213
P13_ST00142 1228 113 within
P13_SP00133 1341
P13_ST00143 1358
P13_SP00134 1419
P13_ST00144 1436 151
P13_SP00135 1587
P13_ST00145 1599 131 glands
P13_SP00136
P13_ST00146 1747
P13_SP00137 1785 11
P13_ST00147 1796 215 Ad5-IL17A
P13_SP00138 2011
P13_ST00148 2026 139
P13_TL00011 1469 1883
P13_ST00149 174 C57BL6 0.92 0000040
P13_SP00139 476 1501
P13_ST00150 102 mice,
P13_SP00140 596 1508
P13_ST00151 616 80 plus
P13_SP00141 696 1510
P13_ST00152 711
P13_SP00142
P13_ST00153 789 201 significant
P13_SP00143 990
P13_ST00154 1005 changes
P13_SP00144 1175 10
P13_ST00155 1185
P13_SP00145
P13_ST00156 1315 89 their
P13_SP00146 1404
P13_ST00157 1418 splenic
P13_SP00147 1559
P13_ST00158 65 ThI
P13_SP00148 1638 1507
P13_ST00159 1648 0.63
P13_SP00149 1669
P13_ST00160
P13_SP00150 1758
P13_ST00161 1775
P13_SP00151 1840 23
P13_ST00162 1863 64
P13_SP00152 1927
P13_ST00163 239 populations,
P13_TL00012 1575 1858
P13_ST00164
P13_SP00153 361 1607
P13_ST00165 380 1583 presence
P13_SP00154 563 1616
P13_ST00166 580
P13_SP00155 617
P13_ST00167 631 circulating
P13_SP00156
P13_ST00168 autoantibodies,
P13_SP00157 1614
P13_ST00169 1173 218 specifically
P13_SP00158
P13_ST00170 1406 ANA,
P13_SP00159
P13_ST00171 1527 detectable
P13_SP00160 1735
P13_ST00172 1753 by
P13_SP00161
P13_ST00173 1813 153 staining
P13_SP00162 1966
P13_ST00174 1984
P13_SP00163 2021
P13_ST00175 2037 HEp-2
P13_TL00013 1680 1879
P13_ST00176
P13_SP00164 390 1712
P13_ST00177 404 1688 was
P13_SP00165 484
P13_ST00178 501 examined.
P13_SP00166 705
P13_ST00179 737 50 To
P13_SP00167
P13_ST00180 805 140 identify
P13_SP00168 945 1721
P13_ST00181 961
P13_SP00169
P13_ST00182 1039
P13_SP00170 1222
P13_ST00183 1240
P13_SP00171 1277
P13_ST00184
P13_SP00172 1719
P13_ST00185 1409
P13_SP00173
P13_ST00186 1487 sera
P13_SP00174
P13_ST00187 prepared
P13_SP00175 1767
P13_ST00188 1784
P13_SP00176 1872
P13_ST00189 1890 106 blood
P13_SP00177
P13_ST00190 2014 167 samples
P13_TL00014 1786 1902
P13_ST00191 175 collected
P13_SP00178 477 1818
P13_ST00192 495
P13_SP00179 582
P13_ST00193 600 each
P13_SP00180
P13_ST00194 712 196 C57BL6J 0.93 00000400
P13_SP00181 908
P13_ST00195 927 1794 132 mouse
P13_SP00182 1059
P13_ST00196 both
P13_SP00183
P13_ST00197 1180 76 pre-
P13_SP00184 1256 1827
P13_ST00198 1273
P13_SP00185 1344
P13_ST00199 1363 330 post-cannulation 0000000000000000
P13_SP00186 1693
P13_ST00200 1709 were
P13_SP00187 1806
P13_ST00201 1822 120 tested
P13_SP00188 1942
P13_ST00202 53 for
P13_SP00189 2013
P13_ST00203 2028 176 reactivity
P13_TL00015 1891 1923
P13_ST00204 1899 45 on
P13_SP00190 347
P13_ST00205
P13_SP00191 490 1932
P13_ST00206 508
P13_SP00192 606
P13_ST00207 636 52 As
P13_SP00193 688
P13_ST00208 presented
P13_SP00194
P13_ST00209 922
P13_SP00195 951
P13_ST00210 970 135 Figure
P13_SP00196 1105
P13_ST00211 4A,
P13_SP00197 1187 1930
P13_ST00212
P13_SP00198 1266
P13_ST00213 1283
P13_SP00199 1368
P13_ST00214 1385
P13_SP00200 1560
P13_ST00215 1577
P13_SP00201 1665
P13_ST00216 195
P13_SP00202 1878
P13_ST00217 1898
P13_SP00203
P13_ST00218 2006 1892
P13_SP00204 2042
P13_ST00219 2056 22 6
P13_SP00205 2078
P13_ST00220 2093
P13_SP00206 2170
P13_ST00221 2187
P13_TL00016 1997
P13_ST00222 2005
P13_SP00207 374 2038
P13_ST00223 391 or
P13_SP00208 431 2029
P13_ST00224 445 one
P13_SP00209 517
P13_ST00225 532 55 wk
P13_SP00210 587
P13_ST00226 604 prior
P13_SP00211 693
P13_ST00227 706 1998
P13_SP00212 741
P13_ST00228 757
P13_SP00213
P13_ST00229 895 191 treatment
P13_SP00214 1086
P13_ST00230 1102 showed
P13_SP00215 1254
P13_ST00231
P13_SP00216 1294
P13_ST00232 1311 148 general
P13_SP00217 1459
P13_ST00233 1475 weakly
P13_SP00218 1613
P13_ST00234 1629 398 diffusedcytoplasmic 0000000000000000000
P13_SP00219 2027
P13_ST00235
P13_TL00017 2102
P13_ST00236 nuclear
P13_SP00220 451
P13_ST00237 233 background
P13_SP00221 2143
P13_ST00238
P13_SP00222 870
P13_ST00239 888
P13_SP00223 926
P13_ST00240 938
P13_SP00224 998
P13_ST00241 1016 185 individual
P13_SP00225 1201
P13_ST00242 2103 116 target
P13_SP00226 1334
P13_ST00243 1349
P13_SP00227 1447
P13_ST00244 1481 However,
P13_SP00228 1666 2141
P13_ST00245 1685 2110
P13_SP00229 1770
P13_ST00246 1787
P13_SP00230 1963
P13_ST00247
P13_SP00231
P13_ST00248 2043
P13_SP00232 2120
P13_ST00249 2137 post-
P13_TL00018 2207 1831
P13_ST00250 2208 192
P13_SP00233 493 2239
P13_ST00251 507
P13_SP00234
P13_ST00252 614
P13_SP00235
P13_ST00253
P13_SP00236 860
P13_ST00254
P13_SP00237
P13_ST00255
P13_SP00238
P13_ST00256 1200
P13_SP00239 1325
P13_ST00257 1339
P13_SP00240 1374
P13_ST00258 1390
P13_SP00241 1411
P13_ST00259 1426
P13_SP00242
P13_ST00260
P13_SP00243 1557
P13_ST00261 2215
P13_SP00244 1643 2248
P13_ST00262 1660
P13_SP00245 1812
P13_ST00263 1832 no
P13_SP00246
P13_ST00264 1894 cytoplasmic
P13_TL00019 2313
P13_ST00265
P13_SP00247 2354
P13_ST00266 471
P13_SP00248 549 2345
P13_ST00267 567 2321 133 course
P13_SP00249 700
P13_ST00268 speckled
P13_SP00250 893
P13_ST00269 911
P13_SP00251
P13_ST00270 1082
P13_SP00252 1153
P13_ST00271 168 negative
P13_SP00253 1340
P13_ST00272 nucleoli,
P13_SP00254 1518 2352
P13_ST00273 1536 while
P13_SP00255
P13_ST00274 1653 Ad5-LacZ
P13_SP00256 1850
P13_ST00275 1865
P13_SP00257 2004
P13_ST00276 2023
P13_TL00020 2418
P13_ST00277
P13_SP00258 2450
P13_ST00278 155 diffused
P13_SP00259 653
P13_ST00279 671
P13_SP00260 909 2459
P13_ST00280 924 164 staining,
P13_SP00261 1088
P13_ST00281 weak
P13_SP00262 1211
P13_ST00282 but
P13_SP00263 1288
P13_ST00283 1302 fine
P13_SP00264 1373
P13_ST00284
P13_SP00265
P13_ST00285 1584 288 nucleoplasmic
P13_SP00266
P13_ST00286 1887
P13_SP00267 2039
P13_ST00287 2055
P13_TL00021 2524 1918
P13_ST00288
P13_SP00268 2565
P13_ST00289 489 nucleoli
P13_SP00269 638 2556
P13_ST00290 (Figures
P13_SP00270 833
P13_ST00291 849 4B
P13_SP00271 904
P13_ST00292 921
P13_SP00272
P13_ST00293 967 54 C).
P13_SP00273
P13_ST00294 1053 Similar
P13_SP00274 1192
P13_ST00295 results
P13_SP00275 1337
P13_ST00296 1352 2532
P13_SP00276 1449
P13_ST00297 1466 seen
P13_SP00277
P13_ST00298 1579
P13_SP00278 1608
P13_ST00299 1627 C7BL6J 0000400
P13_SP00279
P13_ST00300 1816
P13_SP00280
P13_ST00301 whose
P13_SP00281 2053
P13_ST00302 2070
P13_TL00022 2629 1795
P13_ST00303
P13_SP00282 433 2670
P13_ST00304 448 2637
P13_SP00283 545 2661
P13_ST00305 561 transduced
P13_SP00284 783
P13_ST00306 799
P13_SP00285 877
P13_ST00307 894
P13_SP00286 1109
P13_ST00308 1124 2630
P13_SP00287 1249
P13_ST00309 1262
P13_SP00288
P13_ST00310 1316 44
P13_SP00289 1360
P13_ST00311
P13_SP00290 1452
P13_ST00312
P13_SP00291 1506
P13_ST00313
P13_SP00292 1592
P13_ST00314 1610
P13_SP00293 1639
P13_ST00315 1655 which
P13_SP00294 1769
P13_ST00316
P13_SP00295
P13_ST00317 136 pattern
P13_SP00296 2001
P13_ST00318 2017
P13_TL00023 2734
P13_ST00319 236 pronounced
P13_SP00297 539 2775
P13_ST00320 557 2742
P13_SP00298 690 2766
P13_ST00321 707
P13_SP00299 883
P13_ST00322 901
P13_SP00300
P13_ST00323 1069
P13_SP00301 1147
P13_ST00324 1167
P13_SP00302 1212
P13_ST00325 1229
P13_SP00303 1467
P13_ST00326 1482
P13_SP00304 1634
P13_ST00327 1652
P13_SP00305 1723
P13_ST00328 1743
P13_SP00306 1910
P13_ST00329 1929
P13_SP00307
P13_ST00330 2096 2735
P13_SP00308 2131
P13_ST00331 2146
P13_TL00024 2840 1919
P13_ST00332
P13_SP00309 377 2872
P13_ST00333 394
P13_SP00310
P13_ST00334 2848 age,
P13_SP00311 2881
P13_ST00335 547
P13_SP00312 586
P13_ST00336 603 1
P13_SP00313
P13_ST00337
P13_SP00314 641
P13_ST00338 662
P13_SP00315 739
P13_ST00339 2841 292 post-treatment 00000000000000
P13_SP00316
P13_ST00340 1065
P13_SP00317
P13_ST00341 124 4D-F).
P13_SP00318 1380
P13_ST00342 1413 Considering
P13_SP00319
P13_ST00343
P13_SP00320
P13_ST00344 1745 181 functions
P13_SP00321 1926
P13_ST00345
P13_SP00322
P13_ST00346 1995 IL-17A,
P13_SP00323 2879
P13_ST00347 2155 it
P13_SP00324 2174
P13_ST00348 2191 28 is
P13_TL00025 2945 1924
P13_ST00349 205 interesting
P13_SP00325 2986
P13_ST00350 525 2946
P13_SP00326 2977
P13_ST00351 2953 70 see
P13_SP00327 647
P13_ST00352 664
P13_SP00328 685
P13_ST00353 702 gradual
P13_SP00329
P13_ST00354 868
P13_SP00330 939
P13_ST00355 957 118 subtle
P13_SP00331
P13_ST00356 1092 146 change
P13_SP00332 1238
P13_ST00357
P13_SP00333
P13_ST00358 1301 93
P13_SP00334 1394
P13_ST00359 profile
P13_SP00335 1531
P13_ST00360 1547
P13_SP00336
P13_ST00361
P13_SP00337 1807
P13_ST00362 1826 401 cytoplasmicnuclear 0000000000040000000
P13_TL00026 1255 3053
P13_ST00363