Influenza vaccine combined with moderate-dose PD1 blockade reduces amyloid-beta accumulation and improves cognition in APP/PS1 mice
Influenza vaccine combined with moderate-dose PD1 blockade reduces amyloid-beta accumulation and improves cognition in APP/PS1 mice
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流感疫苗联合中等剂量的 PD1 阻断可减少 APP/PS1 小鼠中淀粉样蛋白的积累并改善认知能力
DOI：
10.1016/j.bbi.2020.09.015
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Yao Zhibin
中科院分区：
文献类型：
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作者：
Xing Zhiwei;Zuo Zejie;Hu D;an;Zheng Xiaona;Wang Xiao;Yuan Lifang;Zhou Lihua;Qi Fangfang;Yao Zhibin
免疫功能障碍与阿尔茨海默病（AD）有关，而全身免疫调节可能具有神经保护作用。我们之前的研究结果表明，卡介苗芽孢杆菌的免疫攻击可以通过增强全身免疫系统来减轻动物模型中的AD病理。类似地，独立研究表明，通过阻断PD-1检查点通路来增强全身免疫系统，可以改变AD。在这里，我们假设流感疫苗可以增强中等剂量抗PD-1的功能，因此将它们结合起来可能会减少修饰疾病所需的PD-1抗体的剂量。我们发现，中等剂量的PD-1联合流感疫苗有效地减轻了APP/PS1小鼠的认知缺陷，并阻止了淀粉样蛋白-β的病理积累，其机制依赖于外周单核细胞来源的巨噬细胞进入大脑的募集。清除外周巨噬细胞则会消除其有益作用。此外，通过比较小鼠实质中的CD11b+区室，我们观察到Ly6C+小胶质样细胞的亚群升高，据报道这些细胞来自外周单核细胞。此外，髓源性抑制细胞在使用的转基因模型中强烈升高，并通过联合治疗正常化，表明脑免疫稳态恢复。总之，我们的研究结果表明，通过静脉注射联合中剂量PD-1抑制来恢复大脑免疫可能是一种治疗AD的免疫疗法。
Immune dysfunction is implicated in Alzheimer’s disease (AD), whereas systemic immune modulation may be neuroprotective. Our previous results have indicated immune challenge with Bacillus Calmette-Guerin attenuates AD pathology in animal models by boosting the systemic immune system. Similarly, independent studies have shown that boosting systemic immune system, by blocking PD-1 checkpoint pathway, modifies AD. Here we hypothesized that influenza vaccine would potentiate function of moderate dose anti-PD-1 and therefore combining them might allow reducing the dose of PD-1 antibody needed to modify the disease. We found that moderate-dose PD-1 in combination with influenza vaccine effectively attenuated cognitive deficit and prevented amyloid-β pathology build-up in APP/PS1 mice in a mechanism dependent on recruitment of peripheral monocyte-derived macrophages into the brain. Eliminating peripheral macrophages abrogated the beneficial effect. Moreover, by comparing CD11b+compartments in the mouse parenchyma, we observed an elevated subset of Ly6C+microglia-like cells, which are reportedly derived from peripheral monocytes. In addition, myeloid-derived suppressor cells are strongly elevated in the transgenic model used and normalized by combination treatment, indicating restoration of brain immune homeostasis. Overall, our results suggest that revitalizing brain immunity by combining IV with moderate-dose PD-1 inhibition may represent a therapeutic immunotherapy for AD.