Abstract Author Information

Background. Recent data suggest that interferon (IFN)-y is not an essential mediator of acute rejection but, instead, is critical for the induction of long-term allograft acceptance. The in vivo mechanisms-by which endogenous IFN-y regulates the alloimmune response and thus facilitates the induction of long-term allograft survival are not known.

Methods. We examined long-term cardiac and skin allograft survival, alloantigen-induced T-cell proliferation, and alloantigen-induced T-cell apoptosis in wild-type (IFN-y+/+) and IFN-y gene-knockout (IFN-y-/-) mice treated with either B7-CD28 T-cell costimulation blockade alone or B7-CD28 T-cell costimulation blockade combined with donor splenocyte transfusion.

Results. We found that IFN-y is essential for long-term allograft survival induced by treating mice with either B7- CD28 T-cell costimulation blockade alone or B7-CD28 T-cell costimulation blockade combined with donor splenocyte transfusion. Alloantigen-induced T-cell proliferation in vivo was significantly greater in IFN-y-' - mice than in IFN-y+/+ mice, and T-cell costimulation blockade abrogated alloantigen-induced T-cell proliferation in wild- type mice but failed to do so in mice that lack IFN-y. In contrast, alloantigen-induced T lymphocyte apoptosis in vivo did not differ between IFN-y+/+ and IFN-y-/- mice, and T-cell costimulation blockade enhanced alloantigen- induced T-cell apoptosis in both mouse strains.

Conclusions. These data suggest that endogenous IFN-y facilitates the induction of long-term allograft survival by limiting the proliferation of alloactivated T lymphocytes. The data also suggest that B7-CD28 T-cell costimulation blockade exerts immunosuppressive actions by inhibiting the proliferation of activated T lymphocytes and by promoting their apoptosis.

The Carlos and Marguerite Mason Transplantation Research Center, Renal Division, Department of Medicine and Veterans Affairs Medical Center, Atlanta, Georgia 30033; Internal Medicine Department, Sohag Faculty of Medicine, South Valley University, Sohag, Egypt; and Pathology and Laboratory' Medicine, Veterans Affairs Medical Center and State University of New York, Buffalo, New York 14215

1This work was supported by grants from the Carlos and Marguerite Mason Trust (to F.G.L.), National Institutes of Health (AI41643-01 to F.G.L.), and the Veterans Affairs Merit Review' (to F.G.L.). Dr. Hassan is a recipient of a research scholarship from the Egyptian government. Dr. Ring is a recipient of a research fellowship grant from the National Kidney Foundation.