Induction of tolerance through mixed chimerism for composite tissue allotransplantation: Insights, problems and solutions

Composite tissue allotransplantation (CTA) research faces two critical challenges. Firstly, the most applicable experimental model(s) in which CTA tolerance induction regimens should be characterized and tested requires clarification. Secondly, it has not been determined what would constitute a suitable endpoint for clinical trials of such methodologies before progression toward wider clinical application could be considered appropriate. Currently, the most reliable method to induce CTA tolerance in animals is to establish mixed hematopoietic chimerism using bone marrow transplantation (BMT) from an allogeneic donor. This approach has three important constraints: (i) the requirement for toxic myeloablative conditioning; (ii) a prerequisite 28-day delay period between BMT and CTA; and (iii) the potential for inducing graft-versus-host disease (GVHD). We review the history of chimerism induction for CTA, the strategies that have been proposed to circumvent CTA-related problems, and the insights that have been gained from our own research into these issues. The benefits of vascularized BMT (VBMT) over conventional BMT for inducing CTA tolerance are highlighted. The establishment of mixed chimerism and the induction of tolerance require further research and refinement before they can be applied clinically. A safe and robust method of tolerance induction encourages wider application of reconstructive CTA with fewer ethical obstacles.