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TL1A Expression in Human IBD and Animal Models Bala Manickam Pfizer ACVP-STP fellow, Anatomic pathology resident University of Georgia, Athens GA.

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Presentation on theme: "TL1A Expression in Human IBD and Animal Models Bala Manickam Pfizer ACVP-STP fellow, Anatomic pathology resident University of Georgia, Athens GA."— Presentation transcript:

1 TL1A Expression in Human IBD and Animal Models Bala Manickam Pfizer ACVP-STP fellow, Anatomic pathology resident University of Georgia, Athens GA

2 TL1A & DR3 - Biology Nat Rev Rheumatol. 2010 Feb;6(2):67-8 2 Biochem Pharmacol. 2011 Apr 1;81(7):838-47

3 3 Inflammatory Bowel Disease Human IBD  IBD represents an important chronic disease affecting the GI tract of man and domesticated animal species.  The 2 IBD entities in humans are Crohn’s disease (CD) and Ulcerative colitis (UC).  Immune mediated - responds to immunomodulatory drugs  The pathogenesis of IBD involves: 1.Failure of immune regulation. 2.Genetic susceptibility. 3.Environmental triggers (microbial flora). 4.Disruption of the mucosal barrier. Mouse models of IBD  DSS (Dextran sulphate) colitis: Oral administration of this sulphated polysaccharide to mice induces a self limiting colitis  TNBS (Trinitrobenzene sufonic acid) colitis: Colonic inflammation is induced by intrarectal administration of TNBS dissolved in 50% ethanol Canine IBD  Small intestine: Lymphocytic-plasmacytic enteritis (LPE), eosinophilic enteritis and eosinophilic gastro-enteritis (EGE)  Large intestine; Lymphocytic-plasmacytic colitis, eosinophilic colitis, histiocytic ulcerative colitis (HUC) (mainly PAS-positive macrophages), and regional granulomatous colitis (mainly PAS- negative macrophages )

4 Healthy Person CD UC 4 TL1A & DR3 expression in human IBD TL1A DR3 J Immunol 2003;171;4868-4874

5 Control anti TL1A Mucosal Immunology (2011) 4, 172-185; 5 TL1A & DR3 : Evidence of Efficacy TNBS colitis DSS colitis ControlDR3 KO Gut bacteria GASTROENTEROLOGY 2008;135:552–567

6 Rationale for current study  Up-regulation of TL1A and DR3 in human CD and UC and in rodent IBD models  TL1A and DR3 deficiency attenuates murine IBD  IBD occurs spontaneously in dogs. Because of this, and because it shares a similar immunopathology, it may provide valuable mechanistic insight into the disease in humans.  Studying IBD in spontaneous and induced models may provide insights into how we model the disease in laboratory mice 6

7 Hypothesis  By characterizing and comparing expression profile of TL1A and other critical immunological markers in murine IBD to people, we may further validate (and perhaps even uncover) therapeutic targets for human IBD. 7

8 Objectives  Compare and characterize the staining of TL1A & DR3 in intestinal tissues obtained from DSS and TNBS mouse colitis models, human IBD, canine IBD and normal colons from cynomolgus monkeys.  Compare the staining characteristics of mast cells in intestinal tissues obtained from DSS and TNBS mouse colitis models, human IBD and canine IBD.  Compare the expression of T&B cells in different models of IBD. 8

9 Experimental design GroupsNumber of subjects Number of slides/subject Total number of slides DSS (Mouse) 51050 TNBS (Mouse) 51050 Normal colon (Mouse) 51050 UC (Human) 6636 CD (Human) 6636 Normal colon (Human) 6636 Normal colon (Primate) 5525 IBD (Dog) 51050 Normal colon (Dog) 51050 9

10 Reagents Anti-human TL1A mAb (made by Pfizer, optimized for IHC) –Homology to mouse, rat: 92% –Homology to dog (predicted): 86% Anti-human DR3 mAb (made by Novus Biol) –The immunogenic peptide shares –44% homology with canine DR3 (XP_546752 ) –88% homology with primate DR3 (XM_003274297 CD3, CD45RB220, CD20, Toluidine blue Pfizer Internal Use10

11 11 Normal CD UC Results: TL1A expression Mice Naïve DSS TNBS Human

12 12 Cynomolgus Human Mice Vasculature (+) Results: TL1A expression Germinal center (-) DR3 CD Lamina propria

13 13 Mast cells in IBD – Dog, Mice H&E Naive IBD T-blue Naive DSS TNBS

14 14 B-lymphocytes-Human IBD Germinal center Normal CD UC Lamina propria

15 15 B-lymphocytes-Mice IBD Germinal center Naive DSS TNBS Lamina propria

16 16 T-lymphocytes-Human IBD Germinal center Normal CD UC Lamina propria

17 17 T-lymphocytes-Mice IBD Germinal center Naive DSS TNBS Lamina propria

18 18 B & T lymphocytes- Cynomolgus Germinal center B-cells T-cells Lamina propria

19 19 TL1A:  The expression of TL1A was similar and consistent across the species  TL1A was up regulated in IBD when compared to the Naive/healthy patients  This data not only validates the existing murine IBD models but also indicates that TL1A could be a druggable target in IBD  We also uncovered that Cynomolgus shares similar staining characteristics with human and murine IBD tissues and thus can probably be a good model to study human IBD B&T-lymphocytes:  Increased numbers of both B & T cells in the lamina propria in cases of IBD, suggests a potential role for immune activation in IBD Mast cells:  In our study, We could not detect any difference in the expression of mast cells in both naïve and or IBD patients in both murine and Dog cases. Conclusion

20 20 Acknowledgement  Dr. Timothy LaBranche (Industry Mentor)  Dr. Elizabeth Howerth (Academic Mentor)  Dr. Zaher Radi (Pfizer)  Dr. Shawn O’ Neil (Pfizer)  Jameel Syed (Pfizer)  Zachery Stewart (Pfizer)  University of Georgia  ACVP-STP Coalition  Studies were funded and supported by DRSD, Pfizer

21 Pfizer Internal Use21 Thank you!


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