Transplantation tolerance induced by mixed chimerism.

Although short- and long-term results after organ transplantation have improved considerably in recent years, morbidity and mortality rates in graft recipients remain high. The induction of lifelong donor-specific tolerance would dramatically improve outcome after organ transplantation. Although many tolerance protocols have been successful in rodent studies, most of these approaches have failed when attempted in large animals or humans. Robust tolerance, in contrast, has been demonstrated with mixed chimerism regimens not only in rodents but also in large animal models, including non-human primates. Furthermore, mixed chimerism protocols have been developed that would be feasible in cadaveric, and thus in thoracic, transplantation. The induction of mixed hematopoietic chimerism is therefore an attractive experimental approach for development of clinical tolerance protocols. One of the obstacles to widespread clinical application of this concept is the remaining toxicity of the host conditioning. Recent advances, however, have led to substantially milder protocols that could become clinically acceptable in the foreseeable future. This article provides a short overview of the basic mechanisms by which immunologic tolerance may be induced, describes the concept of mixed chimerism as a promising approach for clinical tolerance induction, and reviews recent progress in developing clinically feasible mixed chimerism protocols.