靶向血管生成素-1的上调可改善早期糖尿病性肾病

Authors
Luigi Gnudi MD, PhD

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”.

1型糖尿病（T1D)是自身反应性T效应器细胞(Teff)和耐受调节性T细胞(Tregs)之间平衡打破之后的病理延续结果。完整的有关这一信号通路的了解更有助于诱导这些自身反应性T细胞的凋亡，产生下一代的稳定Tregs，是T1D治疗策略发展的关键。我们之前已经展示了酰肌醇三磷酸激酶(PI3K)是一种主要的细胞生成通路。和糖尿病-抵抗性C57BL/6 小鼠相比，这一通路在NOD鼠的脾细胞中高度活化。我们已经发现上调细胞磷酸化的一种第二信使，会使得Teff表达上升,而在Tregs细胞这一表达显著下降。这显示对于Teff和Tregs细胞对于PI3K生存和更进一步的抑制有不同的需求，Teff细胞和Tregs细胞相比，更倾向于诱导凋亡。我们因此着眼于利用一种新特异性抑制剂(AS605240)，研发一种新的NOD PI3Kγ-/-鼠来着眼于白细胞受限制的γ亚基PI3K通路AS605240有效地预防和逆转了NOD小鼠的自身免疫学糖尿病。NOD PI3Kγ-/- 鼠显示了100%的30周龄的糖尿病预防率（n=12）。

PI3Kγ抑制有效地抑制了自身免疫性T细胞并且诱导Tregs，通过STAT5 and cAMP反应性结合(CREB)通路分别在体内和体外激活拓展。更多的体外刺激具有胰多肽NOD.PI3Kγ-/-小鼠，和NOD.PI3Kγ+/- and NOD.PI3Kγ+/+小鼠中的T细胞，其自身反应性CD4+ 和CD8+T细胞凋亡明显增加。还有，NOD.PI3Kγ-/-产生的Treg显示和WT相比，其体内和体外的凋亡更少。以白细胞受限制的γ亚基PI3K为靶向可以开展一些还未达到的安全的治疗T1D的治疗策略。PI3Kγ已经对动脉粥样硬化和缺血性心脏病有效果，如果能够预防T1D，它就能叫做“21世纪的阿司匹林”了。

编辑： 黄石    来源：丁香园