IFN-γ Is Critical for Long-Term Allograft Survival Induced by Blocking the CD28 and CD40 Ligand T Cell Costimulation Pathways

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Abstract
It is postulated that IFN-γ production hinders long-term acceptance of transplanted organs. To test this hypothesis, we compared survival of skin and heart allografts in wild-type (IFN-γ+/+) mice to that in IFN-γ gene knockout (IFN-γ−/−) mice. We found that perioperative blockade of the CD28 and/or CD40 ligand T cell costimulation pathways induces long-term skin and heart allograft survival in IFN-γ+/+ recipients but fails to do so in IFN-γ−/− mice or in wild-type mice treated with IFN-γ-neutralizing Ab at the time of transplantation. In vitro studies showed that endogenously produced IFN-γ down-regulates T cell proliferation and CTL generation in MLCs. These actions of IFN-γ were not mediated by TNF-α production or Fas-Fas ligand interactions. In vivo studies revealed exaggerated expansion and, subsequently, impaired deletion of superantigen-reactive T lymphocytes in IFN-γ−/− mice injected with staphylococcal enterotoxin B. Taken together, our findings indicate that IFN-γ does not hinder but instead facilitates induction of long-term allograft survival possibly by limiting expansion of activated T cells.