Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-β burden in several amyloid transgenic mouse models
Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-β burden in several amyloid transgenic mouse models
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DOI：
10.1002/glia.23260
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发表时间：
2018-03-01
期刊：
影响因子：
6.2
通讯作者：
Pradier, Laurent
中科院分区：
文献类型：
--
作者：
Latta-Mahieu, Martine;Elmer, Bradford;Pradier, Laurent
慢性炎症是阿尔茨海默病（AD）发病机制的核心组成部分。最近的工作表明，通过程序性细胞死亡-1（PD 1）检查点抑制打破免疫耐受产生IFN-γ依赖性全身免疫应答，其中脑被外周髓样细胞浸润，并且神经病理学以及功能改善，甚至在患有晚期淀粉样蛋白病理学的小鼠中（Baruch et al.，（2016）：Nature Medicine，22：135-137）。因此，当激活免疫系统是适当的时，免疫检查点抑制被建议作为神经退行性疾病的潜在治疗。由于研究中使用了异种大鼠抗体（mAb），因此该效应是否对PD 1靶点结合具有特异性尚不确定。在本研究中，我们研究了PD 1免疫疗法是否可以降低淀粉样蛋白β病理学在一系列不同的淀粉样蛋白转基因模型中进行了三家制药公司与完全相同的抗PD 1同种型和两个小鼠嵌合变体。尽管PD 1免疫疗法刺激外周免疫系统的系统性激活，但未检测到单核细胞衍生的巨噬细胞浸润到脑中，并且脑淀粉样蛋白病理学的进展未改变。在两个独立机构的另外两个模型中，获得了PD 1免疫疗法对淀粉样蛋白脑病理学影响的类似阴性结果。这些结果表明，PD 1检查点信号传导的抑制本身不足以减少淀粉样蛋白病理，并且其他因素可能有助于先前公布的结果（Baruch et al.，（2016）：Nature Medicine，22：135-137）。在阐明这些因素之前，动物模型数据不支持进一步评估PD 1检查点抑制作为阿尔茨海默病的治疗方式。
Chronic inflammation represents a central component in the pathogenesis of Alzheimer's disease (AD). Recent work suggests that breaking immune tolerance by Programmed cell Death-1 (PD1) checkpoint inhibition produces an IFN-gamma-dependent systemic immune response, with infiltration of the brain by peripheral myeloid cells and neuropathological as well as functional improvements even in mice with advanced amyloid pathology (Baruch et al., (2016): Nature Medicine, 22:135-137). Immune checkpoint inhibition was therefore suggested as potential treatment for neurodegenerative disorders when activation of the immune system is appropriate. Because a xenogeneic rat antibody (mAb) was used in the study, whether the effect was specific to PD1 target engagement was uncertain. In the present study we examined whether PD1 immunotherapy can lower amyloid-beta pathology in a range of different amyloid transgenic models performed at three pharmaceutical companies with the exact same anti-PD1 isotype and two mouse chimeric variants. Although PD1 immunotherapy stimulated systemic activation of the peripheral immune system, monocyte-derived macrophage infiltration into the brain was not detected, and progression of brain amyloid pathology was not altered. Similar negative results of the effect of PD1 immunotherapy on amyloid brain pathology were obtained in two additional models in two separate institutions. These results show that inhibition of PD1 checkpoint signaling by itself is not sufficient to reduce amyloid pathology and that additional factors might have contributed to previously published results (Baruch et al., (2016): Nature Medicine, 22:135-137). Until such factors are elucidated, animal model data do not support further evaluation of PD1 checkpoint inhibition as a therapeutic modality for Alzheimer's disease.