Banff 2003 Liver Session Summary

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Banff 2003Liver Session Summary
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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.
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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.
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Outcomes of Chronic Liver Allograft Rejection

• recovery (n10)
• linger (n7)
• chronic rejection (35 pts)
• failure/death with, but not due to CR
  (n10)
• failure (n8)

Blakolmer et al Transplantation. 2000 Jun
1569(11)2330-6
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Lymphocyte Apoptosis in Human Liver Allograft
Recipients

• Andrew Clouston
• Recipient T cell apoptosis occurs
• Sinusoidal microenvironment important (Kupffers
  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

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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

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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.

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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.

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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

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Hepatic Allograft Rejectionwhen is treatment
necessarythe pathologists 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

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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.

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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

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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 gt AIH gt 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.

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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.

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Plan

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

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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