5. Transplantation tolerance

Abstract

Immune tolerance is the Holy Grail of transplantation. Tolerance allows transplantation without need for lifelong immunosuppression, granting the transplant recipient freedom from rejection of the transplant organ, freedom from the complications of immunosuppression – primarily infection and cancer over time – and freedom from the side effects of the immunosuppressive drugs, which can be serious and compromise the life of the transplant organ and recipient. There are rare instances of spontaneous tolerance in kidney transplantation, in recipients who independently stopped their immunosuppressive medications. Usually withdrawal of these drugs results in rejection and organ loss. Tolerance induction in kidney transplantation today requires transplantation of both hematopoietic cells and kidney from donor to recipient. There are three centers in the United States actively pursuing tolerance induction in this manner. They are the Massachusetts General Hospital, Northwestern, and Stanford. The protocols at the three centers differ in the nature and timing of the hematopoietic cell transplant and in the nature of the conditioning regimen necessary to prepare for hematopoietic cell transplantation. The goal of this approach is the achievement of chimerism – transient, mixed or complete depending on the protocol – which can then allow complete immunosuppressive drug withdrawal. All three centers have attempted tolerance induction in HLA-matched and HLA-mismatched living donor transplantation, with success measured as at least 1 year free of immunosuppression with no rejection and normal transplant kidney function. Both the MGH and Northwestern have been successful in approximately 50% of their HLA-mismatched recipients, while Stanford has been successful in approximately 80% of their HLA-matched recipients. Work continues at all three centers to improve efficacy, safety and durability of this approach to tolerance induction. The Stanford protocol differs from the protocols at the other centers in that the conditioning regimen for the hematopoietic cell transplant begins after transplantation of the kidney, potentially allowing the protocol’s use in deceased donor transplantation. In the protocols employed by the other centers, the conditioning regimen begins several days prior to transplantation of the kidney, restricting these protocols to living donor transplantation. Living donor transplantation is scheduled; deceased donor transplantation occurs urgently, usually well within 24 h of organ availability. Enhanced organ viability and organ banking could expand the applicability of protocols employing the early conditioning regimen for the hematopoietic cell transplant and allow easier implementation of the Stanford protocol in deceased donor transplantation. Furthermore, improved organ viability should result in less delayed and impaired function of the transplant organ, improving its longevity particularly when coupled with a state of tolerance. The ultimate goal is one (transplant) kidney for life.