Achieving permanent transplant tolerance via reverse chimeras in orthotopic liver transplantation

Abstract:The severe side-effects and toxicities associated with lifelong immunosuppression after organ transplantation necessitate the quest for immunological tolerance, it is a durable immunosuppression-free state in which the transplanted allograft functions well without chronic rejection occurrence, and there is no transplant tolerance protocol available clinically. Here we show that this tolerance, during the transition from hypertrophy to hyperplasia upon liver regeneration, is acquired early and maintained permanently in orthotopic rat half-size liver transplantation (LT) while host bone marrow stem cells are mobilized and short-course immunosuppression is administered. Compared with whole and half-size LT as controls, survival for more than 500 days was observed in tolerant rats, the liver allograft worked better and its microstructures remained normal without chronic rejection. Sex-mismatch LT revealed that the host bone marrow stem cells repopulated the allograft to create reverse chimeras with host Y chromosomes in female donor livers and the increased host to donor ratio over time. However, a donor specific hyporesponse was not achieved through skin transplantation and skin allograft challenge did not elicit the rejection of liver allografts. Our finding that transplant tolerance achieved via reverse chimeras bypasses the complex immune system simplifies its induction clinically and facilitates its translation and application in human