Tolerance to organ transplants: Is chimerism bringing it closer than we think?

PURPOSE OF REVIEW: The recent development of novel immunosuppressive agents that target effector cell function has allowed steroid-sparing protocols to promote allograft survival. Although this development is a major step forward, chronic rejection and end-organ toxicity due, to the side-effects of the same agents that are critical to promote graft survival, remain major limitations that result in significant morbidity and mortality in transplant recipients. This review focuses on the translation of research on chimerism and tolerance from mice to large animal models, and focuses on what we can learn from our bone marrow transplantation colleagues. RECENT: The observation that the major role for conditioning is to control host-versus-graft alloimmune responses rather than to prepare vacant niches resulted in a paradigm shift in bone marrow transplantation that allowed reduced-intensity approaches for conditioning for bone marrow transplantation. Immune-base conditioning to control host-versus-graft responses allowed the development of nonmyeloablative hematopoietic stem cell transplant therapies, substantially reducing the toxicity of ablative conditioning. Nonmyeloablative hematopoietic stem cell transplantation is now widely used in humans too old or ill to tolerate ablative bone marrow transplantation for malignancy. Chimerism, and therefore tolerance, is readily established in the clinic. Graft-versus-host disease, however, remains the final challenge to be conquered. SUMMARY: Approaches to establish low levels of mixed donor-host chimerism are currently being translated to pilot studies in humans. Novel tolerogenic cell-based approaches, including graft-facilitating cells, in combination with nonmyeloablative conditioning, may provide the final critical component for safe induction of tolerance to transplanted organs and tissue.