Mixed Chimerism for Tolerance Induction of Vascularized Composite Allografts

Abstract

Vascularized composite allograft (VCA) transplantation offers unparalleled restoration of devastating soft tissue and musculoskeletal defects, but the risk-to-benefit ratio of the necessary lifelong immunosuppression in the management of nonlife supporting transplants remains a cause for concern. Induction of transplant tolerance would permit VCA survival free from long-term immunosuppression. Hematopoietic mixed chimerism has been demonstrated to successfully induce tolerance of various donor tissues and organs in both small and large animal models, and has been successfully applied to clinical practice for induction of renal allograft tolerance. Recent research has demonstrated that tolerance of all components of VCAs can also be achieved using these approaches. We review the mechanisms operational in mixed-chimerism-based tolerance, chiefly deletion, regulation, and anergy; implications of peripheral versus central tolerance; discuss the potential differences between protocols achieving transient and stable mixed chimerism; highlight some issues specific to VCA transplantation due to the unique nature of the composite allograft; and finally outline some practical considerations for further progress in translating research findings to clinical protocols for VCA tolerance.