The impact of targeting CD40-CD154 pathway in nonhuman primate vascularized composite allograft model

Abstract Vascular composite allotransplantation (VCA) is the most immediately available therapy for individuals who have suffered irreparable tissue damages or deformities. While the technical aspects of VCA have rapidly advanced for these patients, the outcomes of VCA still lag behind those of other solid organ transplantation. The dramatic difference in outcomes highlights the inadequacy of current immunosuppressive regimens in VCA, which are largely borrowed from other organ transplantation, particularly kidney transplantation, where patients are immunologically more naïve. The higher immunogenicity (or susceptibility to rejection) of VCA may be attributed to (1) the inclusion of multiple tissues (i.e. muscle, skin, nerve etc.) in the transplant, (2) the exclusive use of deceased donors for VCA, and (3) pre-transplant management of trauma including transfusion prior to VCA. These factors will contribute to VCA rejection by expanding allo-specific immune cell repertoire, priming innate cells (trained immunity), and sensitizing recipients, respectively.We have shown that targeting the CD40/CD154 signaling pathway with anti-CD154mAb successfully promote long-term graft survival of kidney allograft in naïve recipients. Furthermore, anti-CD154mAb showed superior efficacy in sensitized recipients compared to tacrolimus-based conventional immunosuppression. Together with cytolytic induction, anti-CD154mAb effectively prevented post-transplant humoral response, eliminated antibody-mediated rejection (AMR) and significantly prolonged graft survival in sensitized recipients, all without introducing additional viral complications or malignancy. Given its exceptional efficacy in organ transplantation, particularly in sensitized recipients, we hypothesize that targeting the CD40/CD154 singling pathway can efficiently regulate the host immune response following VCA, even in cases where recipient have been sensitized by primary trauma care. This approach may create a therapeutic window to induce donor-specific tolerance. We will evaluate anti-CD154mAb approach in combination with either apoptotic donor cells or complement inhibition to re-establish an immune repertoire that favors transplantation tolerance. To explore this hypothesis, we propose 3 specific aims: 1) To test the efficacy of anti-CD154mAb in a naïve and sensitized nonhuman primate VCA models. 2) To determine efficacy of antigen-specific and non-specific pro-tolerance approaches in NHP VCA recipients. 3) To identify the functional phenotype of allo-specific T and B cells repertoires required to establish tolerance in VCA recipients.