Banff 2003 Liver Session Summary

1. Banff 2003Liver 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. Mod-Sev Mild 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 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, persistingdendritic 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 • Optimum dose and timing • Drug interactions in tolerance

10. Hepatic Allograft Rejectionwhen is treatment necessarythe 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

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