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.Xunrong Luo, MD, PhD Collaborator (0.24 cal mos, 2% effort, separate subcontract), is an Associate Professor of Surgery in Medicine-Nephrology and Microbiology-Immunology at Northwestern University. As nephrologist, she has been involved in kidney and islet transplant research for 14 years. In collaboration with Dr. Miller, she pioneered the translation of ECDI-treated cells from autoimmunity to transplantation in various murine allo- and xeno- transplant models. She authored many publications in this field including a recent review. She has prior experience with non-human primate transplant models from ongoing collaborative studies with Bernhard Hering evaluating the potential of ECDI-treated cells in allo- and xeno- islet transplantation. Dr. Luo will assist Dr. Azimzadeh in the experimental design, data analysis and manuscript preparation related to this application.