Reversibility of cardiac xenograft rejection in primates

More than 500 people died in 1988 because of the shortage of human heart donors. Cardiac xenografts from concordant primates may help to relieve this shortage. Two groups of ABO-matched cynomolgus monkey-to-baboon heterotopic cardiac xenografts were studied. Group 1 (n = 4) control animals had no immunosuppression. Group 2 (n = 6) baboons received cyclosporine, azathioprine, and methylprednisolone acetate. Myocardial biopsy, mixed lymphocyte culture, donor-specific crossmatch, and panel-reactive antibody determinations were performed after transplantation. Biopsy-proven rejection episodes (myocyte necrosis) were treated intravenously with steroids. A follow-up biopsy was performed 7 days after the first biopsy. If rejection persisted, antithymocyte globulin (10 mg/kg/day) was given for 7 days, and another biopsy was performed. Group 1 (control) graft survival was 8, 9, 9, and 10 days (mean, 9 days). Group 2 (immunosuppressed) graft survival was 3, 16, 18, 51, 84, and 392 days (mean, 94 days). Each immunosuppressed baboons' xenograft had myocyte necrosis and variable degrees of edema, cellular infiltrates, and vascular thrombosis consistent with mixed cellular and humoral rejection within 1 week. Only one rejection episode resolved with high-dose steroid therapy alone. Two baboons' rejection episodes resolved with antithymocyte globulin treatments, but rejection recurred in both. Low levels of or delayed progression of panel-reactive antibody was associated with long-term xenograft survival. Severe steroid-resistant rejection with cell-mediated and humoral immune elements developed early in our primate cardiac xenografts despite triple-drug immunosuppression. Use of antithymocyte globulin was associated with temporary resolution of rejection, but progressive increases in lymphocytotoxic antibody led invariably to eventual graft loss despite rare long-term survival.