ABSTRACT
Developing novel treatment concepts to minimize/avoid immunosuppression by induction of immune tolerance represents the prime task in the field of transplantation. Immunosuppression-free allograft survival has been achieved in several small and large animal models as well as in humans in living-related combined kidney and donor bone marrow transplantation via transient or stable mixed hematopoietic chimerism. This is a concept of particular interest in VCA, as component grafts may inherently contain vascularized donor bone marrow and thus a vital bone marrow niche home to donor-derived hematopoietic progenitor cells. However, as living-related transplantation is ethically precluded in VCA, reconstructive transplantation is limited to cadaveric donors and thus extensive pre-transplant preconditioning is not feasible. Recently, we were able to demonstrate immune tolerance in mice using a peri-transplant induction regimen based on high-dose post-transplantation cyclophosphamide treatment (PT/Cy). In the underlying novel approach, we aim to apply the PT/Cy treatment protocol after the use of conventional immunosuppression to induced a state of delayed tolerance in an attempt to bypass limitation of cadaveric donor settings in VCA.
ABSTRACT
Close to 40 of combat injuries sustained in Operation Iraqi Freedom and Operation Enduring Freedom involve severe extremity and craniofacial trauma. For many devastating injuries where conventional reconstruction is not possible, vascularized composite allotransplantation (VCA) has become a viable alternative, providing new, exciting options for Wounded Warriors that could better restore the appearance, anatomy, and function. However, clinical management of these injuries prior to reconstruction frequently requires multiple blood transfusion or skin allografts resulting in the formation of alloantibodies (anti-HLA IgG Abs, donor specific antibodies or DSA) and a high degree of sensitization. The role of DSA and mechanisms of antibody mediated rejection (AMR) in VCA are still largely unknown. To date, there is only one single experimental study published that has recently attempted to define the role of DSA in a rat model of vascularized osteomyocutaneous flap allotransplantation. As such, this project aims to comprehensively investigate the mechanisms and impact of pre-existing and de-novo DSA and AMR in in VCA. The goal is to develop a clinically translatable desensitization protocol that will subsequently broaden the eligible population for reconstructive transplantation to include those patients who have become sensitized to foreign antibodies