Targeted immune therapies in heart transplantation

Abstract Heart transplantation has become the mainstay lifesaving therapeutic strategy for a growing number of patients with irreversible, end-stage heart disease. However, numerous challenges must be met to improve long term heart allograft rejection. Although immune therapeutics (ITs) used to prevent rejection have improved over time, they are still unable to eliminate acute and chronic rejection effectively. The use of more intense and potent IT regimens, adopted commonly by transplant programs, can reduce the survival of heart transplant patients by increasing their chances of developing metabolic syndrome, post-transplant malignancy, and serious infection. Therefore, a significant unmet need exists to develop novel and innovative strategies to increase the efficacy of ITs and to reduce their toxicity. Although targeted drug delivery using nanotechnology or antibody-drug conjugates (ADCs) has sparked great interest in the cancer field, its application to transplantation remains to be developed. Over the past several years, we have made major strides to introduce a wide range of targeted therapeutics to the heart transplantation research field. In transplantation, presentation of donor allo-antigens to recipient T cells in the draining lymph nodes (DLN) is fundamental to the generation of alloreactive T cells that traffic to the allografts and cause rejection. The overall hypothesis of this proposal is that targeted delivery of ITs to the DLN and allografts not only increases the efficacy of ITs, but it also decreases their toxicity through reduction of their systemic dosage. In this proposal, we devise a clinically applicable active targeted delivery method for ITs to LNs and organs to promote allograft acceptance in murine models of heart transplantation. We also plan to examine the operating mechanisms that result in prolongation of heart allograft survival by our active targeted delivery platform. These experiments will employ murine heart transplant models, nanoparticle synthesis, advanced antibody-drug conjugation, comprehensive immune phenotyping assays, and sophisticated imaging studies to understand the kinetics of T cell trafficking and payloads in the tissue. Supported by our extensive expertise, as well as established models, techniques, and data, this multidisciplinary collaborative approach sets forth for the first time a well-balanced, innovative, and clinically applicable targeted delivery platform. The studies proposed here have the potential to yield results that could be paradigm-shifting in our approach to immunosuppressive therapy in transplantation.