Effect Of Kidney Cotransplantation On Induction Of Heart Graft Tolerance In Nonhuman Primates (Nhps)

Introduction: Tolerance has been achieved in NHPs and human recipients of kidney allogeneic transplants through induction of transient hematopoietic mixed chimerism. However, the same approach has failed to induce tolerance of cardiac allografts in primates. In this study, we investigated whether immune regulation induced by kidney allografts in this model could spread to heart transplants from the same donor thereby preventing their rejection in cynomolgus monkeys. Methods: Cynomolgus monkeys underwent donor bone marrow transplantation (DBMT) and either heart/kidney co-transplantation (n=6) or heart transplant alone (n=4) following nonmyeloablative conditioning, which consisted of TBI (1.5 Gy ×2), thymic irradiation (7Gy), horse ATG, anti-CD154 mAb, and a 28-day course of cyclosporine. One monkey received DBMT 4 months after co-transplantation. Results: The majority of recipients of DBMT and co-transplantation of the heart and kidney achieved long-term survival (380*, 391*, >366, >261, 131, >51, >30 days; *[heart rejection after removal of the kidney on day 315]) of both allografts without maintenance immunosuppression. Critical involvement of the kidney allograft in the maintenance of tolerance was clearly demonstrated as heart allograft was rejected shortly after removal of the kidney allograft. In stark contrast, all four monkeys transplanted with an isolated heart acutely rejected shortly after cessation of Cyclosporine. IFNγ-ELISPOT and MLR assays in tolerant recipients showed donor specific hyporesponsiveness. T regulatory cells were found enriched in 7-8 times more in the kidney allograft comparing with those in the peripheral blood. Conclusion: This is the first demonstration of heart allograft tolerance in nonhuman primates. Apparently, the presence of the allogeneic kidney is necessary for the maintenance of tolerance of the transplanted heart. The mechanistic studies suggested that the kidney allograft facilitates to induce/expand specific regulatory T cells induced after transient mixed chimerism.Figure: [Cardiac Graft Survival]