由mTOR信号通路抑制引起的代谢中断 抑制调节性T细胞扩张 临床应用
Roberto Gedaly1,2,3,4, Gabriel Orozco1, Alexandre P Ancheta1,4
1Transplant Division, Department of Surgery, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
Cells
|August 26, 2023
概括
AZD8055通过诱导线粒体应激和扰乱细胞代谢,损害了调节性T细胞 (Treg) 扩张和功能,与拉巴amycin不同. 这一发现对于移植中Treg治疗的发展至关重要.
科学领域:
- 免疫学 免疫学 免疫学
- 细胞生物学 细胞生物学
- 药理学 药理学是指药理学的学科.
背景情况:
- 调节性T细胞 (Treg) 治疗为诱导移植耐受性提供了一个有希望的方法.
- 通过Treg疗法最大限度地降低免疫抑制可以减少患者的药物相关毒性.
研究的目的:
- 评估一种mTORC1/C2抑制剂AZD8055在制造临床级Treg细胞中的疗效.
- 在Treg扩展协议中比较AZD8055与拉帕素 (RAPA) 的作用.
主要方法:
- 人类Treg细胞被分离并评估了生命力,扩张,抑制功能,自,线粒体未折叠蛋白反应 (mitoUPR) 和代谢特征.
- 对AZD8055和RAPA对Treg细胞的影响进行比较分析.
主要成果:
- AZD8055强烈抑制mTORC2信号和IL2受体下游事件比RAPA.
- AZD8055诱导了线粒体呼吸和糖解中的代谢失调,损害了Treg扩张和功能.
- 不同于RAPA,AZD8055影响了自和增强了mitoUPR.
结论:
- 在Tregs中,AZD8055触发了线粒体的压力,功能障碍,自功能受损和生物能干扰.
- 这些影响导致Treg增殖潜力和抑制功能的丧失,与RAPA的影响形成鲜明对比.
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