title: Effector mechanisms of nonsuppurative destructive cholangitis in graft-versus-host disease and allograft rejection.
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.
authors.affiliation: Hepatology, MRC Centre for Immune Regulation, Institute of Biomedical Research, The Medical School, Edgbaston, Birmingham, UK. d.h.adams@bham.ac.uk
authors.forename: David H
authors.initials: DH
authors.lastname: Adams
authors.forename: Simon C
authors.initials: SC
authors.lastname: Afford
mesh_terms: D017209:Apoptosis; D001652:Bile Ducts / Q000166:cytology / Q000473:pathology; D015815:Cell Adhesion Molecules / Q000502:physiology; D053222:Fas Ligand Protein; D006084:Graft Rejection / Q000503:physiopathology*; D006086:Graft vs Host Disease / Q000503:physiopathology*; D006801:Humans; D007165:Immunosuppression Therapy; D008105:Liver Cirrhosis, Biliary / Q000276:immunology* / Q000503:physiopathology; D008562:Membrane Glycoproteins / Q000502:physiology; D018124:Receptors, Tumor Necrosis Factor; D048069:Tumor Necrosis Factors / Q000502:physiology
chemical_list: D015815:Cell Adhesion Molecules; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D018124:Receptors, Tumor Necrosis Factor; D048069:Tumor Necrosis Factors