Long-term Tolerance to Islet Transplantation via Targeted Reduction of beta cell-specific T cells
Type 1 diabetes (T1D) results from insulin insufficiency due to the loss or dysfunction of pancreatic beta cells following T cell-mediated autoimmune attack. Currently, the only long-term therapy is daily exogenous insulin replacement. The ideal curative approach is the durable restoration of functional islets via transplantation with or without immunosuppression or immune modulation. To date, the limiting factors impeding realization of this goal is the lack of a cost effective and limitless source of high-quality islets suitable for transplantation and the ability to provide long-term islet graft acceptance without prolonged need for deleterious immunosuppression. Ongoing clinical trials are testing the suitability of islets derived from human induced pluripotent stem cells (iPSC); however, long-term acceptance of these or any other islet graft will require a clinically effective therapeutic strategy to prevent engrafted islet destruction by pre-existing islet-antigen specific T cells. While current immunomodulatory strategies focus on autologous T regulatory (Treg) cell expansion or the use of broad immunosuppression, here we demonstrate in the NOD mouse model for T1D that autologous islet graft acceptance can be achieved by the targeted elimination of (re)-activated islet-reactive CD4+ and CD8+ T effector (Teff) cells in the initial post-transplantation period by using a short-acting, combination therapy that results in the elimination of islet-reactive Teff cells by exacerbation of their natural DNA damage response (DDR) to drive apoptosis while at the same time maintaining endogenous Treg cell function and reducing the effector function of residual islet-reactive T cells. Overall design: To investigate the ability to target autoreactive CD4+ and CD8+ T cells in islet transplant in diabetic mice. Using a combination p53 potentiator (MDM2 inhibitior, nutlin-3) and cell cycle disruptor (Wee1 inhibitor, MK-1775), serial treatments of new onset diatic NOD mice were treated daily for 3 days with longitudanal sampling of pancretic infiltrating T cells by scRNA-Seq, 1, 2, and 3 days of therapy to assess changes in CD4+ and CD8+ T cells subsets and gene expression.