Accumulation and activation-induced release of preformed Fas (CD95) ligand during the pathogenesis of experimental graft-versus-host disease.

Wasem, Christoph; Frutschi, Corina; Arnold, Diana; Vallan, Claudio; Lin, Tesu; Green, Douglas R; Mueller, Christoph; Brunner, Thomas (2001). Accumulation and activation-induced release of preformed Fas (CD95) ligand during the pathogenesis of experimental graft-versus-host disease. The journal of immunology, 167(5), pp. 2936-2941. American Association of Immunologists 10.4049/jimmunol.167.5.2936

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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.

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