Transcript No Slide Title

Banff 2003
Liver Session Summary
Distribution of Banff Severity of Acute Rejection
Graft Failure from Acute or Chronic Rejection
Gx Fail, 1
575/901 patients
64% developed
any severity of
acute rejection
Bx No. = 2038
Mod-Sev, 26
Mild, 73
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
Acute Rejection
9%
Most patients that
experience acute liver
allograft rejection do
not develop fibrosis in
F/U biopsies
18%
Mod-Sev
14%
Mild
Demetris et al. Real Time Monitoring of Acute Liver Allograft Rejection Using the Banff Schema.
TRANSPLANTATION. 2002; 74(9): 1290-6.
59%
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
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:
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increased chimerism (Day 0 not 1)
increased lymphocyte activation
increased cytokine expression (blood)
reduced acute rejection
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
Role of Macrophages and CD40CD40 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.
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
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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
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Optimum dose and timing
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Drug interactions in tolerance
Hepatic Allograft Rejection
when is treatment necessary
the pathologist’s perspective
• Chris Bellamy
• Immune reactivity after OLTx is a self organizing/selfregulating 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
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.
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
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.
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.
Plan
• Develop consensus document containing
clinicopathologic criteria for the
diagnosis of late liver allograft
dysfunction.
• Review document via the internet and
submit for publication.
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