The effects of tolerance on allograft damage caused by the innate immune system.
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.
Hoerbelt
Ruediger
R
Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Boston, MA 02114, USA.
Benjamin
Christopher L
CL
Shoji
Tsuyoshi
T
Houser
Stuart L
SL
Muniappan
Ashok
A
Hasse
Rebecca S
RS
Ledgerwood
Levi G
LG
Allan
James S
JS
Sachs
David H
DH
Madsen
Joren C
JC
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
D000949:Histocompatibility Antigens Class II; D011994:Recombinant Proteins; D007371:Interferon-gamma