1. Banff 2003 Liver Session Summary

2. Distribution of Banff Severity of Acute Rejection Graft Failure from Acute or Chronic Rejection 575/901 patients 64% developed any severity of acute rejection Bx No. = 2038 Demetris et al. Real Time Monitoring of Acute Liver Allograft Rejection Using the Banff Schema. TRANSPLANTATION. 2002; 74(9): 1290-6.

3. Fibrosis in F/U Biopsies in Pts with Acute Rejection Most patients that experience acute liver allograft rejection do not develop fibrosis in F/U biopsies Mild Mod-Sev Demetris et al. Real Time Monitoring of Acute Liver Allograft Rejection Using the Banff Schema. TRANSPLANTATION. 2002; 74(9): 1290-6.

4. Outcomes of Chronic Liver Allograft Rejection recovery (n=10) linger (n=7) chronic rejection (35 pts) failure/death with, but not due to CR (n=10) failure (n=8) Blakolmer et al Transplantation. 2000 Jun 15;69(11):2330-6

5. Lymphocyte Apoptosis in Human Liver Allograft Recipients Andrew Clouston Recipient T cell apoptosis occurs Sinusoidal microenvironment important ( Kupffer’s cells, endothelial cells, persisting dendritic cells) No role for recipient stem cells in hepatocyte replacement Early PBMC (lymphocyte) apoptosis (D1) increased after OLT associated with: –increased chimerism (Day 0 not 1) –increased lymphocyte activation –increased cytokine expression (blood) –reduced acute rejection

6. Emerging Role of Dendritic Cells in Hepatic Immunity A. Thomson & A.J. Demetris Myeloid and lymphoid DC precursors exist in the normal human liver and develop during necro-inflammatory liver disease. DC can stimulate or subvert T cell responses by inducing immune deviation or regulatory cells DC tolerogenicity can be enhanced by immunologic, pharmacologic or genetic engineering approaches Uptake of apoptotic cells inhibits DC pro-inflammatory function and promotes T cell unresponsiveness

7. Role of Macrophages and CD40- CD40 ligand signaling in Hepatic Allograft Rejection and Injury David Adams CD40-CD40L interactions between liver epithelial cells (hepatocytes and bile duct cells) and macrophages or activated T cells can generate apoptotic signals in cooperation with Fas-FasL signaling Similar signaling in endothelial cells does not lead to apoptosis, but can lead to enhanced survival Unique (fenestrated) sinusoidal endothelium likely of importance in tolerogenic T cell stimulation after liver transplantation.

8. Immunologic Hepatobiliary Injury John Vierling BECs active participants in NSDC (tubulitis): Interplay of Innate and Adaptive Immunity Generation of immunopathology Production of chemokines and cytokines Chemoattraction and activation of inflammatory cells Polarization of Th1 and Tc1 responses Fibrogenesis Chemokines and chemokine receptors potential therapeutic targets in NSDC.

9. Mechanisms of Hepatic Tolerogenecity Alex Bishop Depends on donor leucocytes Other factors: liver vasculature, size Mechanism involves T cell activation and death Inhibited by some immunosuppressive drugs Drugs that least inhibit tolerance l Optimum dose and timing l Drug interactions in tolerance

10. Hepatic Allograft Rejection when is treatment necessary the pathologist’s perspective Chris Bellamy Immune reactivity after OLTx is a self organizing/self- regulating system, but hard to define nodal points on basis of histopathology, alone. Acute rejection not a major problem in liver transplantation –Mild acute rejection may not require treatment. –More severe acute rejection can lead to problems, but incidence is low so predictive value in individual case is weak. Atypical forms/onset of rejection may present a problem –Humoral rejection (C4d staining in paraffin), late onset rejection

11. Pathology of Immunosuppression Weaning after Liver & Kidney Transplantation Pre-transplant immunodepeletion and minimal post-tx immunosuppression with Calcineurin inhibitors can result in a form of allograft acceptance enabling low-dose immunosuppression (once per week). Mechanism of graft acceptance appears to be ignorance, anergy and/or immune regulation. –Non-allo-immune inflammatory activity in the allograft can precipitate rejection in some “tolerant recipients”. –Careful monitoring required Because of regenerative capacity of the liver, tolerance induction trials are less dangerous to the liver graft than other organs –A “liver is different” bias inhibits progress in understanding allograft tolerance.

12. Autoimmune Hepatitis in Hepatic Allografts as Recurrent and New Onset Disease Albert Czaja AIH is a cause of late allograft dysfunction –Codified diagnostic criteria –Genetic factors important –Distinguished from rejection –New therapies can be anticipated Albert Czaja AIH is a cause of late allograft dysfunction –Codified diagnostic criteria –Genetic factors important –Distinguished from rejection –New therapies can be anticipated

13. Clinical Considerations in the Diagnosis of Autoimmune Diseases in Liver Allografts James Neuberger Recurrent autoimmune diseases are an important causes of late liver allograft dysfunction –PSC > AIH > PBC Establishing the Dx is more difficult than before transplantation. Beware of non-specific auto-antibody production after transplantation. Clinico-pathologic correlation needed to establish the diagnosis with certainty.

14. Histopathology of Late Liver Allograft Dysfunction Stefan Hubscher Acute and chronic rejection are uncommon causes of late liver allograft dysfunction. Late onset acute rejection may be more difficult to distinguish from chronic hepatitis. Late allograft pathology is assuming greater importance. –Unexplained or “idiopathic post-transplant hepatitis” an important cause of late liver allograft pathology.

15. Plan Develop consensus document containing clinicopathologic criteria for the diagnosis of late liver allograft dysfunction. Review document via the internet and submit for publication.

16. Suggestions Carefully plain con-current sessions –Increasing number of transplant pathologists who have broad interests Maintain cross-fertilization between organs More attention paid to parenchymal repair mechanisms –Immunology is similar, repair is different