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PD-1+ Monocytes Mediate Cerebral Vasospasm Following Subarachnoid Hemorrhage
Neurosurgery ( IF 4.8 ) Pub Date : 2020-12-28 , DOI: 10.1093/neuros/nyaa495
Christopher M Jackson 1 , John Choi 1 , Denis Routkevitch 1 , Ayush Pant 2 , Laura Saleh 1 , Xiaobu Ye 1 , Justin M Caplan 1 , Judy Huang 1 , Cameron G McDougall 1 , Drew M Pardoll 2 , Henry Brem 1, 3 , Rafael J Tamargo 1 , Michael Lim 1
Affiliation  

BACKGROUND Cerebral vasospasm is a major source of morbidity and mortality following aneurysm rupture and has limited treatment options. OBJECTIVE To evaluate the role of programmed death-1 (PD-1) in cerebral vasospasm. METHODS Endovascular internal carotid artery perforation (ICAp) was used to induce cerebral vasospasm in mice. To evaluate the therapeutic potential of targeting PD-1, programmed death ligand-1 (PD-L1) was administered 1 h after ICAp and vasospasm was measured histologically at the level of the ICA bifurcation bilaterally. PD-1 expressing immune cell populations were evaluated by flow cytometry. To correlate these findings to patients and evaluate the potential of PD-1 as a biomarker, monocytes were isolated from the peripheral blood and analyzed by flow cytometry in a cohort of patients with ruptured cerebral aneurysms. The daily frequency of PD-1+ monocytes in the peripheral blood was correlated to transcranial Doppler velocities as well as clinical and radiographic vasospasm. RESULTS We found that PD-L1 administration prevented cerebral vasospasm by inhibiting ingress of activated Ly6c+ and CCR2+ monocytes into the brain. Human correlative studies confirmed the presence of PD-1+ monocytes in the peripheral blood of patients with ruptured aneurysms and the frequency of these cells corresponded with cerebral blood flow velocities and clinical vasospasm. CONCLUSION Our results identify PD-1+ monocytes as mediators of cerebral vasospasm and support PD-1 agonism as a novel therapeutic strategy.

中文翻译:

PD-1+ 单核细胞介导蛛网膜下腔出血后的脑血管痉挛

背景脑血管痉挛是动脉瘤破裂后发病率和死亡率的主要来源,并且治疗选择有限。目的评价程序性死亡-1(PD-1)在脑血管痉挛中的作用。方法采用血管内颈内动脉穿孔(ICAp)诱导小鼠脑血管痉挛。为了评估靶向 PD-1 的治疗潜力,在 ICAp 后 1 小时施用程序性死亡配体-1(PD-L1),并在双侧 ICA 分叉水平组织学测量血管痉挛。通过流式细胞术评估表达 PD-1 的免疫细胞群。为了将这些发现与患者相关联并评估 PD-1 作为生物标志物的潜力,从外周血中分离出单核细胞,并通过流式细胞术在一组脑动脉瘤破裂患者中进行分析。外周血中 PD-1+ 单核细胞的每日频率与经颅多普勒速度以及临床和影像学血管痉挛相关。结果 我们发现 PD-L1 给药通过抑制活化的 Ly6c+ 和 CCR2+ 单核细胞进入大脑来预防脑血管痉挛。人类相关研究证实,动脉瘤破裂患者外周血中存在 PD-1+ 单核细胞,这些细胞的频率与脑血流速度和临床血管痉挛相对应。结论 我们的结果确定 PD-1+ 单核细胞是脑血管痉挛的介质,并支持将 PD-1 激动作为一种新的治疗策略。结果 我们发现 PD-L1 给药通过抑制活化的 Ly6c+ 和 CCR2+ 单核细胞进入大脑来预防脑血管痉挛。人类相关研究证实,动脉瘤破裂患者外周血中存在 PD-1+ 单核细胞,这些细胞的频率与脑血流速度和临床血管痉挛相对应。结论 我们的结果确定 PD-1+ 单核细胞是脑血管痉挛的介质,并支持将 PD-1 激动作为一种新的治疗策略。结果 我们发现 PD-L1 给药通过抑制活化的 Ly6c+ 和 CCR2+ 单核细胞进入大脑来预防脑血管痉挛。人类相关研究证实,动脉瘤破裂患者外周血中存在 PD-1+ 单核细胞,这些细胞的频率与脑血流速度和临床血管痉挛相对应。结论 我们的结果确定 PD-1+ 单核细胞是脑血管痉挛的介质,并支持将 PD-1 激动作为一种新的治疗策略。人体相关研究证实,动脉瘤破裂患者外周血中存在 PD-1+ 单核细胞,这些细胞的频率与脑血流速度和临床血管痉挛相对应。结论 我们的结果确定 PD-1+ 单核细胞是脑血管痉挛的介质,并支持将 PD-1 激动作为一种新的治疗策略。人体相关研究证实,动脉瘤破裂患者外周血中存在 PD-1+ 单核细胞,这些细胞的频率与脑血流速度和临床血管痉挛相对应。结论 我们的结果确定 PD-1+ 单核细胞是脑血管痉挛的介质,并支持将 PD-1 激动作为一种新的治疗策略。
更新日期:2020-12-28
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