Mechanistic and therapeutic role of regulatory T cells in tolerance through mixed chimerism

Purpose of review Although substantial advances in transplantation medicine have improved short-term graft survival, long-term outcome after organ transplantation is unsatisfactory. The induction of donor-specific tolerance as a potential solution remains an unmet need. Mixed chimerism established through transplantation of donor bone marrow is an appealing tolerance strategy, but widespread clinical application is prevented by the toxicity of recipient conditioning, which is required for achieving bone marrow engraftment. Clonal deletion - both central and peripheral - has long been recognized as a cardinal mechanism in experimental mixed chimerism models. Recent findings Several recent studies have delineated the importance of nondeletional, regulatory mechanisms for the induction of tolerance through mixed chimerism. Moreover, the therapeutic application of recipient regulatory T cells (Tregs) has been combined with the transplantation of donor bone marrow. Such a 'Treg-chimerism' protocol leads to engraftment of conventional doses of fully allogeneic bone marrow and to donor-specific tolerance without the need for any cytotoxic conditioning. Summary Regulatory mechanisms play a major role in mixed chimerism protocols. Treg therapy is exceptionally effective in achieving bone marrow engraftment without cytotoxic recipient treatment, thereby eliminating a major toxic factor preventing widespread application of the mixed chimerism strategy.