Islet transplantation is a potentially curative therapy for Type 1 Diabetes, an autoimmune disease that affects millions. The success of islet transplantation is hampered by T cell mediated rejection and toxicities from the untoward effects of calcineurin inhibitor (CNI) based immunosuppression. CNIs are small molecule phosphatase inhibitors used in transplantation for their potent T cell suppression but they are accompanied by many side effects. Type 1 diabetes and transplant rejection result from a T cell mediated destruction of tissue. T cells require three signals for activation: T cell receptor (TCR) engagement, costimulation provided by CD28-B7 binding, and signaling through the shared IL-2/IL-15 receptor. In order to provide T cell specific immunosuppression, but reduce morbidity related to CNI therapy, the T cell specific costimulation blocker Belatacept was developed. Patients treated with Belatacept after kidney transplant enjoy improved graft survival, kidney function, cardiovascular health and islet function compared to those treated with CNIs. However, patients treated with Belatacept experience higher rates and more severe grades of acute T cell mediated rejection. Recently, our lab has demonstrated a dramatic improvement in allograft survival when we combine costimulatory blockade and anti-CD122 treatments. This not only prolongs graft survival in mice but is also effective in a pre-clinical non-human primate kidney transplant model. In part this treatment was effective because it reduced the number of antigen-specific T cells available for rejection. Importantly IL15 signaling has been shown to be an essential pathway in the development of autoreactive, islet specific T cells in Type 1 Diabetes. Thus, we propose using combined CD122 blockade and costimulation blockade as a strategy to prevent both allo- and autoreactive T cell mediated destruction of transplanted islets. We will first evaluate the efficacy of combined therapy in fully allogeneic nave and autoimmune models of islet transplantation in comparison with costimulation blockade alone. Then we will use the murine OVA TCR transgenic system that has been used extensively in our lab to characterize cellular mechanisms of long-term tolerance induction with this novel combination of anti-CD122 and costimulation blockade. The proposed work will serve as a framework for the applicant's training plan to become a physician-scientist by integrating basic science research with a clinical focus in transplantation. These studies will address end stage kidney disease and endocrine disorders using immunomodulatory therapies.
This proposal is relevant to public health because it investigates the use of a novel humanized therapeutic agent, anti-CD122 which blocks the IL2/IL15 receptor, paired with the most recently approved transplant immunosuppressive agent, Belatacept. This project is relevant to the NIH's mission in that it has the potential to facilitat the development of safe and effective immunosuppression for patients receiving islet replacement therapy for the cure of Type 1 diabetes.
| Mathews, David V; Dong, Ying; Higginbotham, Laura B et al. (2018) CD122 signaling in CD8+ memory T cells drives costimulation-independent rejection. J Clin Invest 128:4557-4572 |
| Jeanneret, Valerie; Ospina, Juan P; Diaz, Ariel et al. (2018) Tissue-type plasminogen activator protects the postsynaptic density in the ischemic brain. J Cereb Blood Flow Metab 38:1896-1910 |
| Mathews, D V; Wakwe, W C; Kim, S C et al. (2017) Belatacept-Resistant Rejection Is Associated With CD28+ Memory CD8 T Cells. Am J Transplant 17:2285-2299 |
| Higginbotham, Laura; Mathews, Dave; Breeden, Cynthia A et al. (2015) Pre-transplant antibody screening and anti-CD154 costimulation blockade promote long-term xenograft survival in a pig-to-primate kidney transplant model. Xenotransplantation 22:221-30 |
