Sensitization and Desensitization in Vascularized Composite Allotransplantation.

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2021-01

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Abstract

Vascularized composite allotransplantation (VCA) is a field under research and has emerged as an alternative option for the repair of severe disfiguring defects that result from severe tissue loss in a selected group of patients. Lifelong immunosuppressive therapy, immunosuppression associated complications, and the effects of the host immune response in the graft are major concerns in this type of quality-of-life transplant. The initial management of extensive soft tissue injury can lead to the development of anti-HLA antibodies through injury-related factors, transfusion and cadaveric grafting. The role of antibody-mediated rejection, donor-specific antibody (DSA) formation and graft rejection in the context of VCA still remain poorly understood. The most common antigenic target of preexisting alloantibodies are MHC mismatches, though recognition of ABO incompatible antigens, minor histocompatibility complexes and endothelial cells has also been shown to contribute to rejection. Mechanistically, alloantibody-mediated tissue damage occurs primarily through complement fixation as well as through antibody-dependent cellular toxicity. If DSA exist, activation of complement and coagulation cascades can result in vascular thrombosis and infarction and thus rejection and graft loss. Both preexisting DSA but especially de-novo DSA are currently considered as main contributors to late allograft injury and graft failure. Desensitization protocols are currently being developed for VCA, mainly including removal of alloantibodies whereas treatment of established antibody-mediated rejection is achieved through high dose intravenous immunoglobulins. The long-term efficacy of such therapies in sensitized VCA recipients is currently unknown. The current evidence base for sensitizing events and outcomes in reconstructive transplantation is limited. However, current data show that VCA transplantation has been performed in the setting of HLA-sensitization.

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10.3389/fimmu.2021.682180

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Moris, Dimitrios, and Linda C Cendales (2021). Sensitization and Desensitization in Vascularized Composite Allotransplantation. Frontiers in immunology, 12. p. 682180. 10.3389/fimmu.2021.682180 Retrieved from https://hdl.handle.net/10161/27252.

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Scholars@Duke

Moris

Dimitrios Moris

House Staff
Cendales

Linda Carime Cendales

Professor of Surgery

Vascularized composite allotransplantation (VCA) refers to the transplantation of multiple tissues, such as skin, muscle, tendon, nerve, and/or bone, as a functional unit (e.g. a hand, an abdominal wall). Several recent advances in clinical organ transplant immunosuppression and experimental VCA have now made it feasible to consider clinical VCA for functional restoration in patients with the loss of one or both hands or large tissue defects that may not be reconstructed with autologous tissue. My research facilitates the translation of VCA from the bench to the bedside.

Our group has established preclinical models to understand VCA rejection in different tissues and to use that insight to minimize immunosuppression in VCA recipients who participate in clinical trials. We also organized the first public international consensus discussions conference in VCA at the Ninth Banff Conference on Allograft Pathology in Spain in 2007 resulting in the Banff VCA 2007 classification for skin allograft pathology. Additionally, we established a VCA Consortium to enable the comprehensive analysis of samples from patients in VCA clinical trials around the country.

Based on our studies of different immunosuppressive regimens in primates, we have been the first to show that belatacept prevents rejection in VCA in primates and controls rejection in humans. We are currently investigating this approach in a clinical trial of hand transplant recipients (NCT02310867). This clinical trial aims to determine the safety and efficacy of hand transplantation as a treatment for patients with limb loss. This study will also test the efficacy of belatacept to prevent rejection of the transplanted hand. We are also currently investigating in a clinical trial the efficacy of abdominal wall transplantation for the reconstruction of abdominal wall defects (NCT03310905).


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