Banff 2003Banff 2003

Liver Session SummaryLiver Session Summary

Distribution of Banff Severity of Acute Rejection Distribution of Banff Severity of Acute Rejection Graft Failure from Acute or Chronic RejectionGraft Failure from Acute or Chronic Rejection

Mild, 73

Mod-Sev, 26

Gx Fail, 1

575/901 patients64% developed any severity ofacute rejectionBx No. = 2038

Demetris et al. Real Time Monitoring of Acute Liver Allograft Rejection Using the Banff Schema.TRANSPLANTATION. 2002; 74(9): 1290-6.

Fibrosis in F/U Biopsies in Pts with Fibrosis in F/U Biopsies in Pts with Acute RejectionAcute Rejection

Most patients thatexperience acute liver allograft rejection donot develop fibrosis in F/U biopsies

59%

14%

18%

9%

Mild

Mod-Sev

Demetris et al. Real Time Monitoring of Acute Liver Allograft Rejection Using the Banff Schema.TRANSPLANTATION. 2002; 74(9): 1290-6.

Outcomes of Chronic Liver Outcomes of Chronic Liver Allograft RejectionAllograft 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

Lymphocyte Apoptosis in Human Lymphocyte Apoptosis in Human Liver Allograft RecipientsLiver 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

Emerging Role of Dendritic Cells in Emerging Role of Dendritic Cells in Hepatic ImmunityHepatic 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

Role of Macrophages and CD40-Role of Macrophages and CD40-CD40 ligand signaling in Hepatic CD40 ligand signaling in Hepatic

Allograft Rejection and InjuryAllograft 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.

Immunologic Hepatobiliary InjuryImmunologic 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

• FibrogenesisChemokines and chemokine receptors potential therapeutic targets in NSDC.

Mechanisms of Hepatic Mechanisms of Hepatic TolerogenecityTolerogenecity

• 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

Hepatic Allograft RejectionHepatic Allograft Rejectionwhen is treatment necessarywhen is treatment necessarythe pathologist’s perspectivethe 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

Pathology of Immunosuppression Pathology of Immunosuppression Weaning after Liver & Kidney Weaning after Liver & Kidney

TransplantationTransplantation• 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.

Autoimmune Hepatitis in Hepatic Autoimmune Hepatitis in Hepatic Allografts as Recurrent and New Allografts as Recurrent and New

Onset DiseaseOnset 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

Clinical Considerations in the Clinical Considerations in the Diagnosis of Autoimmune Diseases Diagnosis of Autoimmune Diseases

in Liver Allograftsin 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.

Histopathology of Late Liver Allograft Histopathology of Late Liver Allograft DysfunctionDysfunction

• 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.

PlanPlan

• Develop consensus document containing clinicopathologic criteria for the diagnosis of late liver allograft dysfunction.

• Review document via the internet and submit for publication.

SuggestionsSuggestions

• 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