title: IFN-gamma is critical for long-term allograft survival induced by blocking the CD28 and CD40 ligand T cell costimulation pathways.
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.
authors.affiliation: The Carlos and Marguerite Mason Transplantation Research Center, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30033, USA.
authors.forename: B T
authors.initials: BT
authors.lastname: Konieczny
authors.forename: Z
authors.initials: Z
authors.lastname: Dai
authors.forename: E T
authors.initials: ET
authors.lastname: Elwood
authors.forename: S
authors.initials: S
authors.lastname: Saleem
authors.forename: P S
authors.initials: PS
authors.lastname: Linsley
authors.forename: F K
authors.initials: FK
authors.lastname: Baddoura
authors.forename: C P
authors.initials: CP
authors.lastname: Larsen
authors.forename: T C
authors.initials: TC
authors.lastname: Pearson
authors.forename: F G
authors.initials: FG
authors.lastname: Lakkis
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage; D018106:CD28 Antigens / Q000276:immunology*; D019013:CD40 Antigens / Q000276:immunology*; D023201:CD40 Ligand; D060908:CTLA-4 Antigen; D017637:Clonal Deletion; D002999:Clone Cells; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D006085:Graft Survival / Q000187:drug effects / Q000235:genetics; D016027:Heart Transplantation / Q000276:immunology; D006801:Humans; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000235:genetics / Q000502:physiology*; D008024:Ligands; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016038:Skin Transplantation / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D019013:CD40 Antigens; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D008024:Ligands; D008562:Membrane Glycoproteins; D023201:CD40 Ligand; D000069594:Abatacept; D007371:Interferon-gamma