干扰PGE2合成/反应途径抑制了编程细胞死亡-1 (Pd-1) 缺陷的高脂血症小鼠中的动脉动脉生成
Emanuela Ricciotti1,2, Soon Yew Tang1, Antonijo Mrčela1
1Institute for Translational Medicine and Therapeutics, Perelman School of Medicine.
bioRxiv : the preprint server for biology
|July 15, 2024
概括
用免疫检查点抑制剂向前列腺素E2通路可能会改善癌症治疗. 破坏mPGES-1或EPr4可以抑制动脉样硬化,并可能降低与PD-1阻塞相关的心血管风险.
科学领域:
- 免疫学 免疫学 免疫学
- 心血管研究研究心血管研究
- 药理学 药理学是指药理学的学科.
背景情况:
- 针对编程细胞死亡1 (PD-1) 的免疫检查点抑制剂 (ICI) 是有效的癌症治疗方法,但面临抗药性.
- 通过E前列腺体受体 (EPr2,EPr4) 发送的前列腺素E2 (PGE2) 信号促进T细胞疲劳,呈现出治疗点.
- 结合ICI与循环氧化酶 (COX) 抑制剂的结合,可能导致心血管不良事件 (AE).
研究的目的:
- 为了比较扰乱PGE2通路对PD-1缺乏小鼠加速动脉样硬化的影响.
- 评估MPGES-1或EPR4抑制对免疫细胞透和心血管风险的影响.
主要方法:
- 使用了患有PD-1缺乏和高脂血症 (Ldlr-/-) 的小鼠.
- 策略包括全球或骨髓细胞特异的mPGES-1枯竭和全球EPr4枯竭.
- 分析了动脉生成,斑块中的免疫细胞种群和PGE2生物合成.
主要成果:
- 所有策略,包括mPGES-1和EPR4向,抑制了动脉动脉生成.
- mPGES-1 枯竭减少了 PGE2 生物合成,而 EPr4 缺乏增加了它.
- 删除mPGES-1减少了中性粒细胞,而删除EPr4减少了巨细胞和增加了斑块中的T细胞.
- EPr4的缺失导致了额外骨髓淋巴细胞构造和脂质失调.
结论:
- 向mPGES-1或EPR4可以抑制淋巴细胞疲劳,并可能减轻心血管免疫相关的PD-1阻塞的AE.
- 在mPGES-1和EPR4向之间观察到对免疫细胞和代谢参数的明显影响.
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