PI3Kγ抑制剂在1型糖尿病中的新型治疗效果

Authors

Jamil R. Azzi MD

Type 1 Diabetes (T1D) is the pathological sequel of a deranged balance between autoreactive pathogenic T effector cells (Teff) and tolerogenic regulatory T cells (Tregs). A thorough understanding of the signaling pathways that preferentially induce apoptosis of these autoreactive T cells but promote generation of stable Tregs is crucial to the development of therapeutic strategies for T1D. We have shown that Phosphatidylinositol-3-kinase (PI3K) a major cellular survival pathway is highly activated in NOD splenocytes compared to diabetes-resistant C57BL/6 mice. While we found an upregulated expression of its secondary messenger the phosphorylated Akt (pAkt) in Teff Tregs showed significantly lower expression. This indicated a different requirement for PI3K in Teff versus Tregs survival and furthermore that inhibition of PI3K may preferentially induce apoptosis of Teff compared to Tregs. We therefore targeted the leucocyte-restricted γ subunit of the PI3K pathway (PI3Kγ) by a novel specific inhibitor (AS605240) and by developing a new NOD.PI3Kγ-/- mouse. AS605240 effectively prevented and reversed autoimmune diabetes in NOD mice while NOD.PI3Kγ-/- mouse showed 100 % protection from diabetes at 30 weeks of age (n=12). PI3Kγ inhibition efficiently suppressed autoreactive T cells and induced Tregs expansion through the activation of STAT5 and cAMP response element-binding (CREB) pathway respectively in vitro and in vivo. Furthermore ex vivo stimulation of NOD.PI3Kγ-/- with pancreatic peptides showed a significant increase in apoptosis of autoreactive CD4+ and CD8+ T cells compared to NOD.PI3Kγ+/- and NOD.PI3Kγ+/+ T cells. Moreover NOD.PI3Kγ-/- generated Tregs showed less apoptosis compared to WT in vitro and in vivo. Targeting the leucocyte-restricted PI3Kγ could address some of the unmet need to develop safer immunomodulatory strategies for T1D. PI3Kγ inhibition has a beneficial effect on atherosclerosis and cardiac ischemia prevalent in T1D and is called the “aspirin of the 21st century”.

编辑： 霄雁    来源：丁香园