阻断NOTCH通路可以抑制大血管血管炎的血管炎症
Kisha Piggott1, Jiusheng Deng, Kenneth Warrington
1Lowance Center for Human Immunology and Rheumatology, Emory University, Atlanta, GA, USA.
Circulation
|January 12, 2011
概括
在巨细胞动脉炎 (GCA) 中阻断NOTCH信号抑制T细胞激活并减少血管炎症. 这种途径调节为大血管血管炎提供了一个有前途的新免疫抑制疗法.
科学领域:
- 免疫学 免疫学 免疫学
- 血管生物学 血管生物学
- 细胞信号传递 细胞信号传递
背景情况:
- 巨细胞动脉炎 (GCA) 是一种严重的自身免疫性血管炎,影响大动脉.
- CD4 T 细胞在 GCA 病原发生过程中至关重要,树突细胞指导它们的分化.
- 目前的GCA治疗依赖于长期的皮质类固醇,需要替代疗法.
研究的目的:
- 调查NOTCH信号通路在GCA病变发生过程中的作用.
- 评估GCA中NOTCH途径抑制的治疗潜力.
主要方法:
- 对NOTCH受体和连接体表达的人类动脉的分析.
- 在炎症血管内的T细胞中NOTCH通路激活的评估.
- 在人性化的小鼠模型中,使用g-分泌酶抑制剂和可溶性配体抑制NOTCH信号的药理抑制.
主要成果:
- 在GCA动脉中,NOTCH通路组件 (受体,Jagged1,Delta1) 的表达高.
- 在大血管血管炎的T细胞中观察到NOTCH激活,但没有观察到小血管血管炎.
- 在小鼠模型中,NOTCH抑制抑制了T细胞激活,减少了血管炎症,并降低了Th17/Th1反应.
结论:
- 在炎症血管壁中,NOTCH-连接物相互作用对T细胞的保留和存活至关重要.
- 准NOTCH信号通路代表了针对像GCA这样的大血管血管炎的新治疗策略.
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