title: Effects of tolerance induction on the actions of interferon-gamma on porcine cardiac allografts.
abstract: It is well known that interferon-gamma (IFN-gamma) not only plays a critical role in antigen-dependent but also in antigen-independent tissue injury; however, it is not clear how tolerance induction affects the actions of IFN-gamma in the transplant setting. To address this question, we compared the effects of IFN-gamma on porcine recipients of near-syngeneic, rejecting, and tolerant heart transplants. IFN-gamma was infused continuously into the left anterior descending artery of hearts transplanted into 3 groups of major histocompatibility complex (MHC) inbred miniature swine, each treated with a 12-day course of cyclosporine A (CyA). Group 1 recipients received a MHC class I disparate heart, group 2 recipients received a near-syngeneic heart, and group 3 recipients were cotransplanted with a MHC class I disparate heart and kidney, which uniformly induces tolerance to both grafts. An additional group of animals was not transplanted but received intracoronary IFN-gamma infusion into their native hearts. IFN-gamma perfusion not only accelerated the acute rejection of MHC class I disparate hearts (mean survival time = 19 +/- 7.21 vs 38 +/- 8.19 days, P = .025), but caused near-syngeneic heart transplants, which otherwise survive indefinitely, to reject within 35 days (n = 3). In contrast, IFN-gamma perfusion had no demonstrable effects on interstitial rejection, the development of vascular lesions, or graft survival in tolerant heart plus kidney allograft recipients (n = 4) or in autologous hearts (n = 2). These results suggest that tolerance induction mitigates the damaging effects of IFN-gamma itself and that the beneficial effects of tolerance induction on acute and chronic rejection may extend to antigen-independent factors like ischemia/reperfusion injury.
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts 02114, USA. madsen@helix.mgh.harvard.edu
authors.forename: R
authors.initials: R
authors.lastname: Hoerbelt
authors.forename: L C
authors.initials: LC
authors.lastname: Benjamin
authors.forename: T
authors.initials: T
authors.lastname: Shoji
authors.forename: D R
authors.initials: DR
authors.lastname: Johnston
authors.forename: A
authors.initials: A
authors.lastname: Muniappan
authors.forename: D A
authors.initials: DA
authors.lastname: Guenther
authors.forename: J S
authors.initials: JS
authors.lastname: Allan
authors.forename: S L
authors.initials: SL
authors.lastname: Houser
authors.forename: J C
authors.initials: JC
authors.lastname: Madsen
mesh_terms: D000818:Animals; D006084:Graft Rejection / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance; D007371:Interferon-gamma / Q000494:pharmacology*; D013552:Swine; D014184:Transplantation, Homologous / Q000276:immunology*
chemical_list: D007371:Interferon-gamma