Porcine kidney and heat transplantation in baboons undergoing a tolerance induction regimen and antibody adsorption

Background. Xenotransplantation would provide a solution to the current sho rtage of organs for transplantation. Our group has been successful in induc ing tolerance in mice and monkey models of allogeneic transplantation. The present study attempts to extend the same tolerance-inducing regimen to a p ig-to-baboon organ transplantation model. Methods. Nine baboons underwent a conditioning regimen (consisting of nonmy eloablative or myeloablative whole body and thymic irradiation, splenectomy , antithymocyte globulin, pharmacologic immunosuppression and porcine bone marrow transplantation [BMTx]), which has previously been demonstrated to i nduce donor-specific allograft tolerance in monkeys. In addition, immunoads orption of anti-alpha Gal antibody (Ab) was performed. Four of the nine bab oons received pig kidney transplants (KTx), and one also underwent repeat t ransplantation with an SLA-matched kidney. Two received heterotopic pig hea rt transplants (HTx). Three baboons underwent conditioning without organ tr ansplantation for long-term studies of natural Ab kinetics. Results, In the three baboons that received the conditioning regimen withou t an organ transplant, immunoadsorption reduced Ab by approximately 90%, bu t recovery of Ab to pretreatment level or higher occurred within 7 days. In contrast, the level of Ab remained low after organ transplant. No Ab to pi g antigens other than alpha Gal was detected in any baboon before or after BMTx, KTx, or HTx. No graft succumbed to hyperacute rejection. KTx function began to deteriorate within 3-6 days, with oliguria and hematuria progress ing to anuria, and the kidneys were excised after 3, 6, 9, 11, and 14 days, respectively. One HTx ceased functioning at 8 days; the second baboon died with a contracting HTx at 15 days. Features of coagulopathy and thrombocyt openia developed in all six transplanted baboons thigh D dimer, prolonged p rothrombin time and partial thromboplastin time, and falling fibrinogen) re sulting in serious bleeding complications in two baboons, one of which died on day 9, Donor organs showed progressive acute humoral rejection with dep osits of IgM, IgG, and complement; a focal mononuclear cellular infiltrate was also observed. The ureter was the earliest structure of the KTx affecte d by rejection, with progression to necrosis. Conclusions. This conditioning regimen prevented hyperacute rejection but w as ineffective in preventing the return of Ab, which was associated with th e development of acute humoral rejection with features of coagulopathy. No baboon developed anti-pig Ab other than alpha Gal Ab. Further modifications of the protocol directed toward suppression of production of Ab are requir ed to successfully induce tolerance to pig organs in baboons.