Induction of Donor-Specific Tolerance with Vascularized Bone Marrow Transplantation

Abstract

Vascularized composite allotransplantation (VCA) has emerged as a viable means of restoring forms and functions in patients with significant tissue defects. However, administration of lifelong immunosuppression in VCA is complicated with side effects and reduces immunocompetence. Inducing donor-specific immune tolerance in VCA can conceivably be the solution to this dilemma. Creating chimerism by means of donor cell transfer and repopulation is proposed to be a powerful and efficient tool to promote donor-specific immune tolerance. In this chapter, we describe the theory and historical perspective in developing mixed chimerism-based tolerance and the transition of using a vascularized bone marrow transplantation (VBMT) strategy from conventional bone marrow transplantation. We elaborate on how the unique characteristics of VBMT with its possession of vascular dependence and intact stromal microenvironment is advantageous in facilitating self-renewing lymphoid cells that participate in tolerance induction with low risk of graft-versus-host disease development. The recent achievements in VBMT research using various animal models and conditioning protocols in order to understand the role of VBMT in promoting mixed chimerism as well as inducing persistent donor-specific tolerance and VBMT applications in the clinic practice are also discussed.