Treg-based therapy and mixed chimerism in small intestinal transplantation: does Treg +BMT equal intestine allograft tolerance?

Small intestinal transplantation (SIT) is a convincing treatment selection for end-stage bowel failure, however, graft rejection and the toxicity associated with the use of non-specific immunosuppression remain the major limitations in SIT. Induction of SIT tolerance through establishment of mixed chimeras is regarded as a robust approach to solve this problem. In rodent models of nonmyeloablative recipient preparation using donor bone marrow transplant (BMT)+costimulatory blockade, deletion of alloreactive T cells played the dominant role in silencing the effector function of graft-rejecting T cells. However, such understanding of the cellular basis for allograft tolerance might be incomplete. Several recent studies demonstrated that regulatory T cells (Tregs) could promote the establishment of allogeneic mixed chimerism as well as the induction of donor-specific tolerance. Treg-based therapy in and of itself is proposed to be a promising non-toxic approach to prevent allograft from rejection. In addition, latest studies showed that, Tregs not only played a critical role in controlling both acute and chronic rejection, but also might contribute to the protection of allograft from ischemia/reperfusion injury (IRI). Taken together, we hypothesize that, co-transplant of donor bone marrow and Tregs specific for alloantigens might be one of the most effective regimens to induce transplantation tolerance, so as to improve the overall outcome of SIT. Although much efforts have been made, a deliberate protocol without toxicity still needs to be developed for the clinical application.