Abstract

Abstract Preserving endogenous insulin production is clinically advantageous and remains a vital unmet challenge in the treatment and reversal of type 1 diabetes (T1D). While broad immunosuppression has had limited success in prolonging the so-called remission period, it comes at the cost of compromising beneficial immunity. Here, we employed an alternate strategy to specifically deplete the activated diabetogenic T cells that drive pathogenesis while preserving not only endogenous insulin production but also protective immunity. Effector T cells, such as diabetogenic T cells, are naturally poised on the edge of apoptosis because of activation-induced DNA damage that stresses the p53 regulation of cell cycle. We have found that the combined use of small molecular inhibitors that further potentiates p53 while inhibiting G2/M cell cycle checkpoint control drives apoptosis of activated T cells in vivo. When delivered at the onset of T1D these inhibitors eliminate diabetogenic effector T cells, prolong remission, preserve functional islets, and protect islet allografts while leaving naïve, memory, and regulatory T cell populations functionally untouched. Thus, the targeted manipulation of p53 and cell cycle checkpoints represents a new therapeutic modality for the preservation of islet beta cells in new onset type 1 diabetes or after islet transplant.

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