Sensitization and Desensitization in Vascularized Composite Allotransplantation

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.

Cellular activation pathways and interaction networks in vascularized composite allotransplantation

“…The B cell-based production of DSAs holds a pivotal role in the overlap of B cell biology and VCA and can be subdivided into preexisting versus de-novo DSAs, with the latter typically occurring within 3 months post-transplantation ( 25 , 40 , 125 , 126 ). In theory, the immunogenic components of VCA grafts (especially skin and mucosal tissue) and the frequently encountered presensitization (i.e., the formation of preformed potentially donor-specific antibodies) of VCA recipients through previous blood transfusions and/or surgical procedures may predispose this patient population to AMR.…”

Immunogenicity and tolerance induction in vascularized composite allotransplantation

“…The presence of C4d deposits is commonly associated with the presence of DSA in SOT and is a diagnostic criteria for classic AMR. Though it should be noted that unlike SOT, C4d deposits in VCA recipients were not associated with DSA, except for one confirmed case of AMR in which the C4d deposit was specific to the allograft and occurred in the presence of DSA ( 59 , 60 ).…”

Exploring Costimulatory Blockade-Based Immunologic Strategies in Transplantation: Are They a Promising Immunomodulatory Approach for Organ and Vascularized Composite Allotransplantation?

“…Recent developments in biomarkers and molecular diagnostics offer more accurate insights into graft health and immune responses. This comprehensive approach is critical for the intricate care needed for VCA recipients to improve graft survival and function [ 4 , 120 , 121 , 148 , 149 ].…”