| Autor: |
Azzi, Jamil, Thueson, Lindsay, Moore, Robert, Abdoli, Rozita, Reijonen, Helena, Abdi, Reza |
| Předmět: |
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| Zdroj: |
PLoS ONE; 1/12/2017, Vol. 12 Issue 1, p1-11, 11p |
| Abstrakt: |
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 γ-subunit of the Phosphoinositide-3-kinase (PI3K), significantly suppress autoimmune-diabetes. To further delineate the mechanisms and the selectivity of specific immune modulation by PI3Kγ-inhibition, we developed a new NOD mouse model of T1D lacking the γ-subunit of PI3K. Strikingly, the loss of PI3Kγ protected 92% of the NOD-mice from developing spontaneous diabetes. The NOD.PI3Kγ-/- mice are protected from insulitis secondary to a defect in CD4 and CD8 autoreactive-T-cells activation and survival. In addition, PI3Kγ-deficiency promoted Treg generation in-vitro and in-vivo. Furthermore, PI3Kγ-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 PI3Kγ pathway in regulating autoimmune-diabetes and provide rationales for future devise of anti- PI3Kγ therapy in T1D. [ABSTRACT FROM AUTHOR] |
| Databáze: |
Complementary Index |
| Externí odkaz: |
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