Factors contributing to the development of chronic rejection in heterotopic rat heart transplantation

The present study was devised to elucidate the influence of immunogenicity, immunosuppression, and ischemia on the development of transplant vasculopathy (TVP) as well as to investigate myointimal proliferation in syngeneic transplantation.

Fischer 344 and Brown Norway rat heart allografts and Lewis isografts were treated with rapamycin or cyclosporine, exposed to 4 hr of cold ischemia, and observed for 100 to 300 days before the incidence and degree of TVP and perivascular infiltration were assessed.

The incidence of TVP in Fischer 344-->Lewis allografts (rapamycin, 0.5 mg/kg for 14 days) rose steadily, with dense mononuclear infiltration present in coronary lesions at all times (from 10+/-2% at 50 days to 85+/-15% at 150 days). Increased immunogenicity (Brown Norway-->Lewis) intensified TVP (62+/-13%) as compared with its control (25+/-15%, P<0.005). Enhanced immunosuppression (rapamycin, 0.5 mg/kg daily) decreased the incidence of TVP (22+/-11%, P<0.005), and additional low-dose cyclosporine was ineffective (1.5 mg/kg daily, 40+/-14%, NS). Four hours of cold ischemia before transplantation failed to have any effect on allografts, but promoted TVP in isografts (0 vs. 11+/-8%).

The antigenic stimulus has probably the most important impact on the development of TVP, but is not necessarily essential. In most allografts, TVP probably reflects ongoing sublethal acute rejection, whereas myointimal proliferation in isografts presumably results from a perioperative antigen-independent response-to-injury mechanism.