IFN-γ is critical for long-term allograft survival induced by blocking the CD28 and CD40 ligand T cell costimulation pathways

BT Konieczny, Z Dai, ET Elwood, S Saleem… - The Journal of …, 1998 - journals.aai.org
BT Konieczny, Z Dai, ET Elwood, S Saleem, PS Linsley, FK Baddoura, CP Larsen
The Journal of Immunology, 1998journals.aai.org
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 …
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.
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