Abstract
It is postulated that IFN-gamma production hinders long-term acceptance of transplanted organs. To test this hypothesis, we compared survival of skin and heart allografts in wild-type (IFN-gamma+/+) mice to that in IFN-gamma gene knockout (IFN-gamma-/-) 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-gamma+/+ recipients but fails to do so in IFN-gamma-/- mice or in wild-type mice treated with IFN-gamma-neutralizing Ab at the time of transplantation. In vitro studies showed that endogenously produced IFN-gamma down-regulates T cell proliferation and CTL generation in MLCs. These actions of IFN-gamma were not mediated by TNF-alpha production or Fas-Fas ligand interactions. In vivo studies revealed exaggerated expansion and, subsequently, impaired deletion of superantigen-reactive T lymphocytes in IFN-gamma-/- mice injected with staphylococcal enterotoxin B. Taken together, our findings indicate that IFN-gamma does not hinder but instead facilitates induction of long-term allograft survival possibly by limiting expansion of activated T cells.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Abatacept
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Animals
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Antigens, CD
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Antigens, Differentiation / administration & dosage
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CD28 Antigens / immunology*
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CD40 Antigens / immunology*
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CD40 Ligand
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CTLA-4 Antigen
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Clonal Deletion
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Clone Cells
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Cytotoxicity, Immunologic / drug effects
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Graft Survival* / drug effects
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Graft Survival* / genetics
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Heart Transplantation / immunology
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Humans
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Immunoconjugates*
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Immunosuppressive Agents / administration & dosage*
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Injections, Intraperitoneal
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Interferon-gamma / genetics
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Interferon-gamma / physiology*
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Ligands
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Lymphocyte Activation* / drug effects
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Male
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Membrane Glycoproteins / antagonists & inhibitors*
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C3H
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Mice, Inbred C57BL
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Mice, Knockout
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Skin Transplantation / immunology
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T-Lymphocytes / immunology*
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T-Lymphocytes, Cytotoxic / immunology
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Transplantation, Homologous
Substances
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Antigens, CD
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Antigens, Differentiation
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CD28 Antigens
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CD40 Antigens
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CTLA-4 Antigen
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CTLA4 protein, human
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Ctla4 protein, mouse
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Immunoconjugates
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Immunosuppressive Agents
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Ligands
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Membrane Glycoproteins
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CD40 Ligand
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Abatacept
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Interferon-gamma