Successful cardiac xenogeneic transplantation in primates using total lymphoid irradiation

Abstract

Combined total lymphoid irradiation (TLI) and cyclosporine (CyA)dramatically prolong cardiac xenografts in small animals. In order toevaluate this immunosuppressive regimen in primates, heterotopic cardiaccervical xenografts were implanted in a monkey-to-baboon model. Thefollowing groups evolved: group 1 (n = 2) control, no immunosuppression;group 2 (n = 4) CyA and steroids; group 3 (n = 2) preoperative TLI (800 radtotal); group 4 (n = 4) TLI combined with CyA and steroids as in groups 2and 3. Complement-dependent cytotoxicity, mixed lymphocyte culture, cellmediated cytotoxicity as well as myocardial biopsies were periodicallymonitored. A Muga scan was performed at 1 year posttransplant to assessventricular function. Cardiac xenograft survival was best in group 4animals (108, 184, 480, 540 days) compared with 5 and 7 days in the controlgroup. In group 2, graft survival was 13, 17, 18 and 63 days. TLI aloneprolonged survival up to 28 and 29 days. Hemorrhage and myocyte necrosiswere seen in all rejected grafts of group 1, 2 and 3 animals. Mononuclearcell infiltrate and fibrosis were present in group 4 grafts at rejection.High antibody titers (1:256 to 1:512) were detected at rejection only ingroup 1, 2 and 3 animals. This suggests that the combined use of TLI andCyA substantially prolongs xenograft survival in a primate model bypreventing early antibody-mediated rejection as well as by limitingcellular response.