Extending Remission and Reversing New-Onset Type 1 Diabetes by Targeted Ablation of Autoreactive T Cells

Abstract

Preserving endogenous insulin production is clinically advantageous and remains a vital unmet challenge in the treatment and reversal of type 1 diabetes. Although broad immunosuppression has had limited success in prolonging the so-called remission period, it comes at the cost of compromising beneficial immunity. Here, we used a novel 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 (Teff) 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 the cell cycle. We have found that using small molecular inhibitors that further potentiate p53 while inhibiting the G2/M cell cycle checkpoint control drives apoptosis of activated T cells in vivo. When delivered at the onset of disease, these inhibitors significantly reduce diabetogenic Teff cells, prolong remission, preserve functional islets, and protect islet allografts while leaving naive, 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 β-cells in new-onset type 1 diabetes or after islet transplant.

Variable frequencies of peripheral T-lymphocyte subsets in the diabetes spectrum from type 1 diabetes through latent autoimmune diabetes in adults (LADA) to type 2 diabetes

“…Indeed, our analysis of CD4 + T-cell subsets showed that IFN-g + T cells represent the majority of CD4 + Teff cells. Published data support a pathogenic role for Teff cells in T1D, and ablation of Teff cells could significantly preserve b-cell function (29). Importantly, T1D patients receiving islet or pancreas allografts still had an association with autoimmunity recurrence years after disease onset, indicating the possibility of long-lasting autoimmunity of pathogenic T cells in autoimmune diabetes (30).…”

“…Theoretically, activated, but not naïve, Teff cells drive diabetes pathogenesis ( 28 ). Selective depletion of Teff cells prolonged disease remission and preserved islet function in NOD mice ( 29 ). Moreover, memory T cells could be a reserve force to damage β cells in the relapse of autoimmunity.…”