Composite tissue allotransplantation : functional, immunological and ethical aspects

Abstract

Composite tissue allotransplantation (CTA) is a new therapeutic modality to reconstruct large tissue defects of the face, larynx, and extremities. The research in this thesis focuses on various aspects of CTA, i.e. 1) immunosuppression regimens and their influence on bone quality, 2) induction of transplantation tolerance through chimerism, 3) prevention of graft-versus-host disease (GVHD), 4) ethical questions particularly related to hand and face transplantation, and 5) technical feasibility of facial transplantation. The authors investigated different immunosuppressive regimens in rat and porcine CTA models. In particular the effect of immunosuppressants on bone quality was investigated. From these studies we concluded that the drugs preventing allograft rejection decrease bone quality within the allograft and therefore it is advised to monitor bone quality posttransplantation in order to prevent CTA failure. A promising approach to eliminate the need for toxic immunosuppressants is through the induction of transplantation tolerance via bone marrow (BM) transplantation, which results in hematopoietic stem cell chimerism. However, using a rat hind limb transplantation model, the authors demonstrated that tolerant mixed allogeneic [ACI?WF] chimeras were susceptible to GVHD caused by the immunocompetent donor cells transferred with the allograft. Irradiation prior to transplantation prevents GVHD and permits rejection-free graft acceptance. Using this model we successfully developed a clinical relevant protocol in which induction of mixed allogeneic chimerism through BM transplantation could be performed simultaneously with graft transplantation. In further studies we defined the role of the BM and lymph nodes (LNs) within the allograft in causing GVHD. Lymphadenectomy prior to rat hind limb allotransplantation prevented GVHD and demonstrated that chimeric hosts are susceptible to GVHD due to the immunocompetent cell load provided by the LNs and not the BM. In addition, we developed a free vascularized LN transplantation model and demonstrated that the LN microenvironment made a manifest difference between induction and absence of GVHD in chimeric hosts. In the future, when clinical immunological tolerance will be achieved in humans, these data provide a safe and effective way to avoid GVHD. However, to date toxic immunosuppressants are a necessity in preventing rejection. Therefore many argue that the risks posed by these drugs do not justify the benefits of these non-lifesaving CTA procedures. To objectively assess this ethical issue the authors designed a psychometrically reliable and valid instrument containing 237 standardized questions to measure the relative risk that individuals are willing to accept in order to receive the benefits of various CTA procedures. We investigated the level of risk acceptance for the seven transplant procedures (foot, single hand, double hand, larynx, kidney, hemiface, and full face) in organ transplant recipients who live with the risks of immunosuppression, individuals with facial disfigurement, and healthy individuals. From these studies we concluded that certain CTA procedures convey benefits to recipients that are perceived by subjects, to warrant the risks of these procedures, thereby providing a more solid foundation for widespread clinical introduction of this new reconstructive modality. This will move the horizons of plastic surgery towards a new era.