Accelerated rejection of Fas ligand-expressing heart grafts

The Fas/Fas ligand (FasL) system plays an important role in the induction o f lymphoid apoptosis and has been implicated in the suppression of immune r esponses. Recently, there has been renewed interest in immune privilege, as it was shown that two privileged sites (the eye and testes) constitutively express FasL, which kills lymphoid cells that invade these areas. We have established murine FasL-transgenic mice (B6) under the control of the cardi ac alpha-myosin heavy chain promotor, and transplanted FasL-expressing F-1( B6 x C3H/HeJ) heart grafts into syngeneic (F-1) and allogeneic (C3H/HeJ) re cipients. FasL-expressing F-1 heart allografts placed in C3H/HeJ recipients as well as FasL-expressing F-1 isografts placed in nontransgenic and FasL- transgenic F-1 were more rapidly rejected, and their survival was much shor ter than that of nontransgenic control F-1 allografts placed in C3H/HeJ. Na tive control and FasL-expressing hearts looked normal in mice up to 8 wk of age on hematoxylin-eosin staining. Control heart allografts undergoing ord inally acute rejection showed moderate focal lymphocyte infiltrates, while FasL-expressing F-1 allografts and isografts showed massive hemorrhage, ede ma, and massive neutrophil infiltration as early as 1 day after transplanta tion. In conclusion, FasL expression and surgical procedure (ischemia/reper fusion) were synergistic in the induction of accelerated heart graft reject ion, while allogenicity was not necessary. It may be necessary to find ways of controlling neutrophilic reaction/apoptosis in infiltrating lymphocytes to use FasL in clinical organ transplantation.