title: The effects of tolerance on allograft damage caused by the innate immune system.
abstract: BACKGROUND
  It is not known whether tolerance can be induced in a strong proinflammatory milieu or whether the induction of tolerance can prevent interferon (IFN)-gamma-associated graft injury. To address these questions, we studied the effects of rIFN-gamma infusion on porcine cardiac allograft survival.
  
  
  METHODS
  Recombinant interferon (rIFN)-gamma was continuously infused into the left anterior descending artery of hearts transplanted into major histocompatibility complex-inbred miniature swine treated with a 12-day course of cyclosporine A. Group 1 recipients received a nearly syngeneic heart, group 2 recipients received a class I disparate heart, and group 3 recipients were cotransplanted with a class I-disparate heart and kidney, a procedure demonstrated to induce tolerance to both grafts. A fourth group of animals were not transplanted but received intracoronary rIFN-gamma infusion into the native heart.
  
  
  RESULTS
  rIFN-gamma perfusion not only accelerated the acute rejection of class I-disparate hearts (mean survival time, 19+/-7.21 vs. 38+/-8.19; P=0.025) but caused near-syngeneic heart transplants, which otherwise survived indefinitely, to reject within 35 days. In contrast, rIFN-gamma perfusion had no demonstrable effects on hearts grafts in tolerant recipients or on autologous hearts.
  
  
  CONCLUSIONS
  These results suggest that tolerance induction can occur in the presence of IFN-gamma-mediated inflammation, and that tolerance induction can prevent the tissue injury caused by the overproduction of IFN-gamma. This suggests that the beneficial effects of tolerance may include protection from nonspecific inflammatory responses, such as those produced by ischemia-reperfusion injury and brain death.
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
authors.forename: Ruediger
authors.initials: R
authors.lastname: Hoerbelt
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Benjamin
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Shoji
authors.forename: Stuart L
authors.initials: SL
authors.lastname: Houser
authors.forename: Ashok
authors.initials: A
authors.lastname: Muniappan
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Hasse
authors.forename: Levi G
authors.initials: LG
authors.lastname: Ledgerwood
authors.forename: James S
authors.initials: JS
authors.lastname: Allan
authors.forename: David H
authors.initials: DH
authors.lastname: Sachs
authors.forename: Joren C
authors.initials: JC
authors.lastname: Madsen
mesh_terms: D000208:Acute Disease; D000818:Animals; D003331:Coronary Vessels / Q000276:immunology; D004727:Endothelium / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology; D016027:Heart Transplantation / Q000276:immunology; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007113:Immunity, Innate / Q000276:immunology*; D007261:Infusions, Intra-Arterial; D007371:Interferon-gamma / Q000008:administration & dosage / Q000276:immunology; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000276:immunology; D013552:Swine; D013556:Swine, Miniature; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D000949:Histocompatibility Antigens Class II; D011994:Recombinant Proteins; D007371:Interferon-gamma