| First Author | Azzi J | Year | 2017 |
| Journal | PLoS One | Volume | 12 |
| Issue | 1 | Pages | e0169695 |
| PubMed ID | 28081180 | Mgi Jnum | J:247984 |
| Mgi Id | MGI:5919058 | Doi | 10.1371/journal.pone.0169695 |
| Citation | Azzi J, et al. (2017) PI3Kgamma Deficient NOD-Mice Are Protected from Diabetes by Restoring the Balance of Regulatory to Effector-T-Cells. PLoS One 12(1):e0169695 |
| abstractText | 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 gamma-subunit of the Phosphoinositide-3-kinase (PI3K), significantly suppress autoimmune-diabetes. To further delineate the mechanisms and the selectivity of specific immune modulation by PI3Kgamma-inhibition, we developed a new NOD mouse model of T1D lacking the gamma-subunit of PI3K. Strikingly, the loss of PI3Kgamma protected 92% of the NOD-mice from developing spontaneous diabetes. The NOD.PI3Kgamma-/- mice are protected from insulitis secondary to a defect in CD4 and CD8 autoreactive-T-cells activation and survival. In addition, PI3Kgamma-deficiency promoted Treg generation in-vitro and in-vivo. Furthermore, PI3Kgamma-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 PI3Kgamma pathway in regulating autoimmune-diabetes and provide rationales for future devise of anti- PI3Kgamma therapy in T1D. |
