Tolerogenic delivery of donor antigens for cardiac allograft protection

The major limitation of modern organ transplantation is its dependence on long-term immunosuppression, which introduces complications while providing only limited success in the prevention of chronic allograft rejection. The induction of donor-specific immune tolerance remains a primary objective of human transplantation, and preclinical transplant research. The use of carbodiimide (ECDI) treated leukocytes has been developed as an antigen-specific, effective tolerogenic immunotherapy in murine models of autoimmunity and transplantation, and is currently in a phase II clinical trial for the treatment of multiple sclerosis. Here, we propose to evaluate the use of allogeneic ECDI-treated donor leukocytes (allo-ECDI-SP), added in the context of a tolerogenic immunomodulatory treatment regimen, as a strategy for inducing antigen-specific tolerance in a pre-clinical cardiac allograft model. EDCI-treated cell infusions will be explored in the context of an established immunomodulatory regimen targeting the costimulatory molecule CD40 which by itself prevents acute cardiac allograft rejection but does not prevent chronic rejection. Results from these pre-clinical studies will provide key knowledge about the relevance, feasibility and efficacy of this therapy to protect allogenic solid organ transplants for future transitioning into clinical practice.