INTERFERON-GAMMA (IFNγ) IS REQUIRED FOR LONGTERM ALLOGRAFT SURVIVAL INDUCED BY COMBINED ADMINISTRATION OF DONOR-SPECIFIC SPLENOCYTE TRANSFUSION(DSST) AND CTLA4Ig.

Abstract

433 Administration of donor splenocytes or bone marrow enhances the salutary effect of B7-CD28 costimulation blockade on allograft survival in rodents. Because IFNγ has important immunoregulatory functions, we addressed whether this cytokine plays a role in DSST+CTLA4Ig-mediated immunosuppression by comparing the survival of fully allogeneic cardiac or skin grafts in wildtype (IFNγ+/+) recipients to that in IFNγ gene-knockout(IFNγ-/-) mice. DSST (1 × 107 donor splenocytes) was administered i.v. at the time of transplantation. CTLA4Ig (200μg) was administered i.p. in a single dose two days after transplantation. Cardiac rejection was defined as cessation of palpable heart beat and was confirmed histologically. Skin rejection was defined as >90% necrosis of the graft(trunk skin). Results: DSST+CTLA4Ig-mediated prolongation of cardiac allograft survival (C3H/He → BALB/c) was significantly greater in IFNγ+/+ than IFNγ-/- recipients:TableThese data are consistent with our previous findings that endogenous IFNγ facilitates induction of longterm cardiac allograft survival in mice treated with CTLA4Ig alone. Similarly, DSST+CTLA4Ig-mediated prolongation of skin allograft survival(BALB/c → C57BL/6), although modest, was significantly greater in IFNγ+/+ than IFNγ-/- recipients:TableConclusions: (1) Endogenous IFNγ does not hinder but rather facilitates induction of longterm allograft survival in mice treated with donor-specific splenocyte transfusion and CTLA4Ig. (2) These preliminary data suggest that IFNγ plays an essential regulatory role in alloimmunity. Because cyclosporine inhibits IFNγ production, cyclosporine could abrogate the potential clinical utility of donor blood, bone marrow, or splenocyte administration to recipients of solid organ allografts.