Effector Mechanisms of Nonsuppurative Destructive Cholangitis in Graft-Versus-Host Disease and Allograft Rejection

David H. Adams; Simon C. Afford

doi:10.1055/s-2005-916320

Seminars in Liver Disease, Inhaltsverzeichnis

Semin Liver Dis 2005; 25(3): 281-297
DOI: 10.1055/s-2005-916320

Effector Mechanisms of Nonsuppurative Destructive Cholangitis in Graft-Versus-Host Disease and Allograft Rejection

David H. Adams¹ ^, ² , Simon C. Afford²

¹Professor of Hepatology, MRC Centre for Immune Regulation, Institute of Biomedical Research, The Medical School, Edgbaston, Birmingham, United Kingdom
²Liver Research Group, MRC Centre for Immune Regulation, Institute of Biomedical Research, The Medical School, Edgbaston, Birmingham, United Kingdom

Abstract

ABSTRACT

The biliary epithelium provides a physical barrier to ascending infection from the gastrointestinal tract and is also involved in actively regulating the immune response to invading pathogens. Cholangiocytes secrete chemokines and express adhesion molecules that attract effector leukocytes and promote the clearance of infected cells. However in the context of transplantation these properties make cholangiocytes targets for allogeneic cytotoxic T cells, and both graft-versus-host disease and liver allograft rejection are characterized by destruction of intrahepatic bile ducts by infiltrating lymphocytes. The mechanisms of cholangiocyte killing are complex but involve activation of apoptosis by the granzyme/perforin pathway and by activation of death receptors belonging to the tumor necrosis factor (TNF) receptor superfamily, most notably Fas. Fas-dependent apoptosis is carefully regulated by cooperative interactions with other TNF receptors, particularly CD40, that act to amplify autocrine and paracrine expression of Fas ligand and Fas-mediated killing. A better understanding of the molecular control of these processes may explain why bile duct loss continues despite conventional immunosuppression in the vanishing bile duct syndromes, and lead to novel therapies aimed at switching off the chronic inflammatory response and protecting cholangiocytes from apoptosis.

KEYWORDS

Liver allograft rejection - GVHD - apoptosis - vanishing bile duct syndrome - Fas - CD40

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Referenzen

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David H AdamsM.D.

Liver Research Group, MRC Centre for Immune Regulation, Institute of Biomedical Research (Fifth Floor) Wolfson Drive

The Medical School, Edgbaston, Birmingham

B15 2TT, United Kingdom

eMail: d.h.adams@bham.ac.uk