Mixed chimerism through donor bone marrow transplantation: a tolerogenic cell therapy for application in organ...

Organ transplantation is the state-of-the-art treatment for end-stage organ failure; however, long-term graft survival is still unsatisfactory. Despite improved immunosuppressive drug therapy, patients are faced with substantial side effects and the risk of chronic rejection with subsequent graft loss. The transplantation of donor bone marrow for the induction of mixed chimerism has been recognized to induce donor-specific tolerance a long time ago, but safety concerns regarding toxicities of current bone marrow transplantation (BMT) protocols impede widespread application.

Recent studies in nonhuman primates and kidney transplant patients have demonstrated successful induction of allograft tolerance even though--in contrast to murine models--only transient chimerism was achieved. Progress toward the development of nontoxic murine BMT protocols revealed that Treg therapy is a potent therapeutic adjunct eliminating the need for cytotoxic recipient conditioning. Furthermore, new insight into the mechanisms underlying tolerization of CD4 and CD8 T cells in mixed chimeras has been gained and has identified possible difficulties impeding clinical translation.

This review will address the recent advances in murine models as well as findings from the first clinical trials for the induction of tolerance through mixed chimerism. Both the potential for more widespread clinical application and the remaining hurdles and challenges of this tolerance approach will be discussed.