Tolerance induction in clinical transplantation

Introduction of modern immunosuppressive agents has led to great success of allotransplantation in humans, and survival rates for all solid organs have been dramatically improved. However, a constant proportion of organs is lost every year due to chronic allograft rejection and immunosuppressive drug toxicity. This has led to a situation where, despite the of donor organ shortage, about one third of the patients on the kidney transplant waiting list are listed for a retransplant. The induction of donor-specific tolerance has the potential of at least partially resolving this problem, since it might prevent chronic rejection and drug toxicity at the same time. For a variety of protocols, successful tolerance induction has been demonstrated in rodent models. However, translation of such protocols to large animal models and on clinical trials has turned out to be very difficult. This review briefly describes mechanisms and barriers to transplantation tolerance, and then focuses on pre-clinical and clinical studies in non-human primates and humans. We have divided the strategies into two groups, based on the principle mechanisms of tolerance induction: the first group are protocols not using hematopoietic stem cell transplantation (HCT) as part of there regimen. They rely mainly on intensive T cell depletion (either by total body irradiation, total lymphoid irradiation or treatment with T cell-depleting agents such as anti-thymocyte globulin, anti-CD52 antibody or CD3 immunotoxin), which have been combined with costimulatory blockade, signaling blockade or donor antigen infusion. The second group are HCT-based protocols combining HCT with T cell-depleting agents and cytoreductive treatment. So far, only two protocols (one with total lymphoid irradiation and anti-thymocyte globulin, but no HCT; one with HCT, cyclophosphamide, anti-thymocyte globulin and thymic irradiation) have been translated into successful human studies. We summarize and discuss the results of these trials and suggest goals for further studies for the development tolerance protocols applicable for a broad population of allograft recipients.