Accumulation and activation-induced release of preformed Fas (CD95) ligand during the pathogenesis of experimental graft-versus-host disease.
Fas (CD95/APO-1) ligand (FasL)-mediated cytotoxicity has been implicated in tissue destruction in a variety of diseases, including acute graft-vs-host disease (GVHD). In this study, we have analyzed FasL expression and regulation during the course of experimental murine acute GVHD. Although activation-induced FasL-mediated cytotoxicity in control T cells was sensitive to the immunosuppressant cyclosporin A, we observed that functional FasL expression of GVHD T cells became increasingly cyclosporin A unresponsive. This was found to be the result of a massive in vivo accumulation and intracellular storage of FasL protein and its release in a transcription- and protein synthesis-independent manner. Immunohistochemistry analysis of FasL expression in situ revealed accumulation of FasL-expressing cells in the spleen, the liver, and small intestine, with a typical cytoplasmic and granular expression pattern. Thus, we conclude that the release of preformed FasL by infiltrating donor T cells may contribute to recipient tissue damage during the pathogenesis of acute GVHD.
Wasem
C
C
Division of Immunopathology, Institute of Pathology, University of Bern, Bern, Switzerland.
Frutschi
C
C
Arnold
D
D
Vallan
C
C
Lin
T
T
Green
D R
DR
Mueller
C
C
Brunner
T
T
D000208:Acute Disease; D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000209:etiology* / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007421:Intestine, Small / Q000187:drug effects / Q000276:immunology; D008099:Liver / Q000187:drug effects / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D009928:Organ Specificity; D013154:Spleen / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D019014:fas Receptor / Q000378:metabolism*
D007166:Immunosuppressive Agents; D019014:fas Receptor; D016572:Cyclosporine