1. BACKGROUND ON PANCREAS HISTOLOGICAL FINDINGS: University of Maryland experience John C. Papadimitriou, M.D.,Ph.D. Professor of Pathology

2. Experimental models of acute pancreas allograft rejection SEPTAL INFLAMMATION  VENOUS ENDOTHELIITIS AND INFLAMMATION OF DUCTS ACINAR INFLAMMATION INFLAMMATION OF ARTERIAL BRANCHES Allen et al: Am J Pathol 1991,138:303 Schulak et al: Surgery 1995,98:330. Steineger et al: Am J Pathol 1986,124:253. Carpenter et al: Transplantation 1989,48:764.

3. GRADING ACUTE REJECTION 0 No inflammation IMinimal septal inflammation IIVenous, ductal, focal acinar inflammation IIIMultifocal acinar inflammation IVIntimal arteritis/ transmural arteritis VParenchymal necrosis (Drachenberg et al.: Transplantation 1997;63:1579-86)

4. Background Histologic grading of acute allograft rejection in pancreas needle biopsy: correlation to serum enzymes, glycemia, and response to immunosuppressive treatment. (Papadimitriou JC et al.: Transplantation. 1998 Dec 27;66(12):1741-5. )

5. Background Progressive graft sclerosis/chronic rejection (CR) determines the useful lifespan of technically successful pancreas allografts. Episodes of acute rejection are suspected to result in accelerated graft sclerosis.

6. Chronic rejection/graft sclerosis Histological correlate: Increasing fibrosis Clinical correlate: Progressive deterioration of glucose metabolism requiring return to insulin dependence (graft loss).

7. March 2002 April 2002 May 2002

8. Objective of the current study To understand better the relationship between histological features of acute rejection and the development of graft sclerosis.

9. Materials and Methods Comparison of biopsy findings Pancreas tx functioning >36 months (n=33) Pancreas tx with histological and clinical chronic rejection leading to graft failure (n=27)

10. Materials and Methods  Included patients with > 3 months of function (technically succesful)  Excluded  technical complications  pancreatic or abdominal infection at the time of biopsy  lymphoproliferative disorder  recurrence of original disease  lack of biopsy material  All bx were done for allograft dysfunction

11. Materials and Methods: Biopsy Evaluation Grading of acute rejection (Grades 0-V)  Mean rejection grade Individual histological findings  Acinar inflammation (focal vs diffuse)  Venulitis  Ductal inflammation  Eosinophils  Arterial inflammation

12. Comparison of Groups I and II Group I, n=33 (function) Group II, n=27 (chronic rejection) Transplant type8 PAK, 9 PTA, 16 SPK7 PAK, 7 PTA, 13 SPK (NS) Transplanted before 1996 33.3 % 37.0 % (NS) Mean (median) tx lifeMean 2736 (±301.5) days 1333 (±1167) days (p=.0000) Number of biopsies/ Time biopsy n=71 (2.15/pt) mean -13 months n=91 mean 3.37/pt (p=.0027) 18 months - NS

13. Mean grade of acute rejection (0-V) All bx with preserved function: 1.61 (± 1.64) All bx with chronic rejection: 2.55 (±.8) p=.0000 Patients with preserved function: 1.32 (± 0.9) Patients with chronic rejection: 2.57 (±.66) p=.0000 RESULTS

15. FOCAL ACINAR INFLAMMATION DIFFUSE ACINAR INFLAMMATION

21. Conclusions Histological findings in bx for graft dysfunction strongly correlate with long-term outcome. Diffuse acinar inflammation is the most common finding associated with chronic rejection.

22. Conclusions (Cont….) Inflammation involving only fibrous septa (sparing acini and arteries) may be responsive to antirejection treatment and/or may not lead to graft sclerosis.