The novel therapeutic effect of phosphoinositide 3-kinase-[gamma] inhibitor AS605240 in autoimmune diabetes.(ORIGINAL ARTICLE)

Type 1 diabetes (T1D) remains a major health problem worldwide, with a steadily rising incidence yet no cure. Phosphoinositide 3-kinase-[gamma] (PI3K[gamma]), a member of a family of lipid kinases expressed primarily in leukocytes, has been the subject of substantial research for its role in inflammatory diseases. However, the role of PI3K[gamma] inhibition in suppressing autoimmune T1D remains to be explored. We tested the role of the PI3K[gamma] inhibitor AS605240 in preventing and reversing diabetes in NOD mice and assessed the mechanisms by which this inhibition abrogates T1D. Our data indicate that the PI3K[gamma] pathway is highly activated in T1D. In NOD mice, we found upregulated expression of phosphorylated Akt (PAkt) in splenocytes. Notably, T regulatory cells (Tregs) showed significantly lower expression of PAkt compared with effector T cells. Inhibition of the PI3K[gamma] pathway by AS605240 efficiently suppressed effector T cells and induced Treg expansion through the cAMP response element-binding pathway. AS605240 effectively prevented and reversed autoimmune diabetes in NOD mice and suppressed T-cell activation and the production of inflammatory cytokines by autoreactive T cells in vitro and in vivo. These studies demonstrate the key role of the PI3K[gamma] pathway in determining the balance of Tregs and autoreactive cells regulating autoimmune diabetes.