Effect of graft preservation and IgM depletion on guinea pig to rat cardiac xenograft survival

Background. Heterotopic guinea pig (GP) cardiac xenografts (XG) are hyperacutely rejected within minutes when transplanted into rats. Methods. In this GP to rat cardiac XG model, we studied the effect on graft survival of a short cold preservation time (1 hr at 4 degrees C) in the presence or absence of rat anti-GP IgM preformed antibodies. The complete depletion of circulating IgM was obtained by two intraperitoneal injections of anti-rat IgM monoclonal antibody (MARM-4) on preoperative days -3 and -1. Results. When the GP cardiac XG was cold preserved for 1 hr before transplantation, the mean graft survival time (MST) was 13.5+/-2.8 min, whereas without previous cold preservation, the MST was significantly prolonged to 51.5+/-12.3 min (P<0.001). Interestingly, the complete depletion of preformed circulating IgM before grafting significantly prolonged the MST of a cold-preserved XG to 37.1+/-11.3 min in comparison with a nondepleted recipient of a cold-preserved XG (P<0.02), but did not prolong the graft survival of a XG that was not cold preserved (42.5+/-14.1 min). To assess the effect of cold preservation and/or ischemia reperfusion, we intravenously injected a superoxide-dismutase mimetic (EUK-134) just before transplantation of a cold-preserved XG;. This antioxidant regimen improved the MST from 13.5+/-2.8 min to 35.3+/-7.3 min (P<0.001). These results clearly suggested that either preservation lesions or preformed IgM are capable of accelerating the loss of the cardiac graft function, but also that the presence of preformed IgM seems to be especially deleterious when the cardiac XG has previously been ischemically injured. Analyzing the histological data, we also observed that the prompt cessation of cardiac function seen in cold-preserved grafts was uniformly associated with massive interstitial hemorrhage, thereby suggesting a particular susceptibility of the CP cardiac XG to cold preservation. To assess the effect of preservation on the GP cardiac function in a nonimmunological model, we performed syngeneic GP cardiac grafts and found that 1 hr of cold preservation provoked massive interstitial hemorrhage capable of promptly inducing the cessation of the heartbeat. Conclusions. Overall, this study demonstrated that both ischemic lesions and immunological processes might induce the cessation of cardiac graft function in the GP to rat model and this cessation of graft function is probably often misinterpreted as a XG rejection only.