Preclinical and clinical studies on the induction of renal allograft tolerance through transient mixed chimerism.

PURPOSE OF REVIEW The present review updates the current status of research for induction of tolerance through a mixed chimerism approach in nonhuman primates and humans. RECENT FINDINGS Allograft tolerance has been successfully achieved with a nonmyeloablative conditioning regimen and donor bone marrow transplantation in human leukocyte antigen (HLA)-matched and mismatched kidney transplantation. In HLA-matched kidney transplantation, persistent mixed chimerism and renal allograft tolerance has been achieved in some patients. In HLA-mismatched combinations, induction of persistent mixed chimerism has not been achieved using a nonmyeloablative preparative regimen. Nevertheless, the transient mixed chimerism that has been achieved has resulted in long-term renal allograft tolerance in the majority of patients. Recent preclinical studies have demonstrated that the presence of heterologous memory T-cell responses observed in primates, but not in rodents, may be a major barrier for induction of durable chimerism and tolerance in primates. Strategies to overcome such memory T-cell responses may, therefore, be of great value in the development of reliable protocols for clinical tolerance induction. SUMMARY Induction of tolerance in clinical kidney transplantation has been achieved via mixed chimerism approaches. Improvements in the consistency and safety of tolerance induction and extension of successful protocols to other organs and to organs from deceased donors will all be among the next steps in bringing tolerance to a wider range of clinical applications.