PI3K? Deficient NOD-Mice Are Protected from Diabetes by Restoring the Balance of Regulatory to Effector-T-Cells.

ABSTRACT: With a steady increase in its incidence and lack of curative treatment, type 1 diabetes (T1D) has emerged as a major health problem worldwide. To design novel effective therapies, there is a pressing need to identify regulatory targets controlling the balance of autoreactive to regulatory-T-cells (Tregs). We previously showed that the inhibition of the ?-subunit of the Phosphoinositide-3-kinase (PI3K), significantly suppress autoimmune-diabetes. To further delineate the mechanisms and the selectivity of specific immune modulation by PI3K?-inhibition, we developed a new NOD mouse model of T1D lacking the ?-subunit of PI3K. Strikingly, the loss of PI3K? protected 92% of the NOD-mice from developing spontaneous diabetes. The NOD.PI3K?-/- mice are protected from insulitis secondary to a defect in CD4 and CD8 autoreactive-T-cells activation and survival. In addition, PI3K?-deficiency promoted Treg generation in-vitro and in-vivo. Furthermore, PI3K?-inhibitor (AS605240) inhibited proliferation and cytokine production of a human CD4+ T-cell clone specific for GAD555-567 peptide that was isolated from a patient with T1D. These studies demonstrate the key role of the PI3K? pathway in regulating autoimmune-diabetes and provide rationales for future devise of anti- PI3K? therapy in T1D.

SUBMITTER: Azzi J 

PROVIDER: S-EPMC5231340 | biostudies-literature | 2017

REPOSITORIES: biostudies-literature