Hurdles to the induction of tolerogenic mixed chimerism

To date, organ transplant patients have to deal with the numerous side effects of life-long dependence on immunosuppressive drugs, whereas at the same time these drugs fail to prevent chronic rejection in many cases. Finding ways to establish donor-specific immunological tolerance thus remains one of the major goals in transplantation medicine. Tolerance through mixed chimerism can be achieved in rodents and in humans by the transplantation of hematopoietic stem cells. Widespread clinical application of this tolerance approach is, however, prevented by the toxicities of current bone marrow transplantation protocols in humans. Cytotoxic recipient conditioning and the hazard of graft-versus-host disease are unacceptable risks for organ transplant recipients. However, considerable progress has been made toward nontoxic conditioning regimens in animal studies. Translation of these findings into large animal models and the clinical setting is expected to be an important step toward broad clinical application of the mixed chimerism approach in organ transplantation.