Fas-mediated liver damage in MRL hemopoietic chimeras undergoing lpr-mediated graft-versus-host disease.
Fas is an apoptosis-signaling receptor that triggers cell death upon binding to its ligand (FasL). Autoimmune-prone MRL/lpr mice, characterized by a spontaneous mutation of Fas, exhibit a defect in the activation-induced cell death of mature T cells through a Fas-mediated pathway. As a consequence of this defect, activated T cells accumulating in this strain overexpress the FasL and can therefore mediate in vitro Fas-dependent cytotoxicity. To determine whether hepatic injury could be the result of an interaction between T lymphocytes bearing FasL and Fas-expressing liver cells, the livers of lethally irradiated MRL+/+ recipients reconstituted with MRL/lpr lymphoid cells were studied. After transfer of MRL/lpr spleen cells, livers were infiltrated by polyclonal CD8+ T lymphocytes of lpr origin with a peak on day 21 postgrafting. These donor-derived intrahepatic lymphocytes overexpressed the FasL and exerted in vitro Fas-mediated cytotoxicity against Fas+ thymocytes, which was specifically inhibited by soluble recombinant Fas in a dose-dependent manner. These intrahepatic lymphocytes induced apoptosis in vitro, irrespective of MHC restriction, in Fas-expressing primary cultured hepatocytes. Histologic examination of the liver revealed severe endothelialitis as well as periportal and intralobular infiltrations of activated lymphocytes with apoptotic hepatocytes in their vicinity. Simultaneously, liver damage was ascertained by elevated serum transaminase levels. These observations support the notion that an Ag-independent mechanism involving FasL may play a role in certain liver pathologies.
Bobé
P
P
INSERM U267, Villejuif, France.
Bonardelle
D
D
Reynès
M
M
Godeau
F
F
Mahiou
J
J
Joulin
V
V
Kiger
N
N
D000818:Animals; D017209:Apoptosis / Q000276:immunology*; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D006410:Hematopoiesis / Q000235:genetics / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D008099:Liver / Q000276:immunology / Q000473:pathology*; D051379:Mice; D019463:Mice, Inbred MRL lpr; D018183:Transplantation Chimera; D019014:fas Receptor / Q000276:immunology*
D019014:fas Receptor