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Fas‐mediated cholangiopathy in the murine model of graft versus host disease

Bile‐duct injury observed in hepatic graft versus host disease (GVHD) is regarded as an immune‐mediated injury, although its precise mechanism is unclear. However, recent studies have suggested the involvement of Fas‐mediated cell death in this immune‐mediated cholangiopathy. In this study, we first showed the constitutive expression of Fas receptor by cholangiocytes in situfrom normal BALB/c mice, which was upregulated in GVHD mice. Also, we confirmed the Fas protein expression in the isolated cholangiocytes from normal BALB/c mice by immunocytochemistry and immunoblotting. Furthermore, the addition of agonistic Fas antibody–(Jo2)‐induced cholangiocyte apoptosis confirmed by DNA‐ladder formation and annexin V staining. Cholangiocytes from Fas‐deficient mice (MRL lpr/lpr) did not show Jo2‐induced apoptosis. Interferon‐γ augmented Fas expression and Fas‐mediated cell death, respectively. Following these observations, experimental GVHD was induced by transfer of splenocytes from B10.D2 mice to irradiated (800 rad) BALB/c mice. Liver‐infiltrating lymphocytes from the recipient showed dose‐dependent cytotoxicity against 51Cr‐labeled cholangiocytes isolated from BALB/c mice. Moreover, the addition of blocking Fas‐Fc fusion protein reduced this cytotoxicity to 44.7%. Finally, administration of this Fas‐Fc protein to the BALB/c mice, which had been adoptively transferred with splenocytes of B10.D2 mice, prevented the development of hepatic GVHD in vivo. These results showed the involvement of Fas‐mediated cell death in cholangiopathy observed in GVHD, and a soluble Fas‐Fc protein may have a therapeutic potential for hepatic GVHD.