Long-term Tolerance to Islet Transplantation Via Targeted Reduction of Beta Cell-specific T Cells

Article Highlights: Activated beta-cell reactive CD4 and CD8 T effector cells undergo a profound DNA-damage response which is targetable by small molecule inhibitors of the p53 and cell cycle pathways that lead to apoptosis. The use of a combination of MDM2 and WEE1 inhibitors, which termed "p53 potentiation with checkpoint abrogation" (PPCA), conferred significant therapeutic efficacy in treating mouse models of new onset T1D. Specific targeting of these T effector cells by PPCA results in a loss of inflammatory T cell subsets, notably proliferation CD4 Th0 and Th1 subsets and CD8 T effector memory cells, as determined by single cell RNA-seq studies with the preservation of T regulatory cells. When autologous islet grafts are given to established diabetic NOD mice, a single course of PPCA results in long-term islet graft acceptance, restoration of normoglycemia and loss of beta cell specific CD4 and CD8 T cells. PPCA shows promise as a potential means of estimating islet graft tolerance in T1D recipients of islet graft transplantation.