Dr Allister Grant Consultant Hepatologist University Hospitals Leicester

1. The extra-intestinal manifestations of IBD Dr Allister Grant Consultant Hepatologist University Hospitals Leicester

2. Aims • Ease you in • Explain the adhesion cascade • Explain how adhesion molecules introduce tissue specific homing properties to activated lymphocytes • Experimental data/techniques • Anti-adhesion/inflammation strategies in IBD

3. Inflammatory Bowel Disease

4. Erythema Nodosum Pyoderma Gangrenosum

5. Episcleritis

6. Ankylosing spondylitis

7. Cirrhosis Expanded Portal Tracts (Blue)

8. BACKGROUND Inflammatory Bowel Disease and PSC Incidence of IBD = 3-9 per 100 000 Prevalence of IBD = 40-200 per 100 000 2-10% of patients with IBD will subsequently develop PSC ~ 70% of patients with PSC have evidence of IBD 20-40% of patients with end stage PSC develop cholangiocarcinoma

9. Lymphocytes on endothelium

10. The Adhesion Cascade

11. Blood Flow 1. Rolling on Selectins Margination of Lymphocytes Blood Endothelium Tissue

24. Endothelial Cell PNAd mucin E-selectin P-selectin L-selectin CLA mucin PSGL-1 mucin LYMPHOCYTE

25. 2. Lymphocyte Activation

26. Chemokine family of cytokines • Small 8 - 12 kD proteins • Over 50 human chemokines • Produced by many cell types • Secreted in large quantities • Rapid effect on target cells by activating specific G-protein linked receptors • Ability to trigger adhesion in seconds

27. Chemokines a-sub family b-sub family C C CXC CC C C IL-8 ENA-78 GRO MCP-1 MIP-1a MIP-1b RANTES IP-10 HuMIG ITAC

28. Proteoglycans in the endothelial glycocalyx retain and present chemokines to lymphocytes Integrin activation Cytoskeletal reorganisation Migration Lymphocyte Endothelium

29. 3. Firm Adhesion

30. Endothelial Cell VCAM-1 ICAM-1 a b Inactive integrin Active LFA-1 Active a4ß1 LYMPHOCYTE

31. Integrins Addressins Activation signal Arrest of Lymphocytes on Integrins

32. Ctyoskeletal Rearrangement

43. (Chemokine Mediated) 4. Transmigration

44. Adhesion cascade Blood Flow Lymphocyte Endothelium Tethering Rolling Arrest & Activation Transmigration Selectins Integrins Integrins & Chemokine receptors Chemokine receptors Carbohydrate ligands Addressins Addressins & Chemokines Chemokines

45. Thymocytes BLOOD THYMUS Naïve T cells TISSUE LYMPH NODE DC DC BLOOD Memory lymphocytes Effector T cells

46. Memory T cell Skin TISSUE SPECIFIC HOMING OF MEMORY EFFECTOR T LYMPHOCYTES I Weissman, E Butcher, C Mackay, S Shaw and S Jalkanen BLOOD TISSUE BLOOD Lymph Node Naïve T cell Memory T cell Gut

47. Tissue specific T cell recruitment Memory/effector T cell Naïve T cell CCR7 + L-selectin CCR4 + CLA CCR9 + a4b7 PNaD CCL21(SLC) E-selectin CCL17(TARC) MAdCAM-1 CCL25(TECK) LYMPH NODE SKIN GUT

48. Blood Flow Lymphocyte Endothelium Tethering & Rolling Activation Arrest CCR5 VAP-1 receptor VAP-1 receptor ? ? CCR5 ligands glycocalyx VAP-1 VAP-1 Liver

49. EXPRESSION OF VAP-1 IN HUMAN ENDOTHELIUMSalmi et al. J. Ex. Med.1993; McNab et al Gastro 1996 NORMAL INFLAMED LIVER vascular ++ + sinusoidal +++ +++ LYMPH NODE +++ +++ GUT _ +++ KIDNEY + + SKIN _ ++ SYNOVIUM _ ++ BRAIN __ HEART + +

50. MAdCAM-1 Expression in PSC Liver Grant et al Hepatology 2001, Hillan et al Liver 1999 Positive Staining of Portal Vascular Endothelium