A Novel Partial MHC Class II Construct, DRmQ, Inhibits Central and Peripheral Inflammatory Responses to Promote Neuroprotection in Experimental Stroke
A Novel Partial MHC Class II Construct, DRmQ, Inhibits Central and Peripheral Inflammatory Responses to Promote Neuroprotection in Experimental Stroke
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DOI：
10.1007/s12975-019-00756-1
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发表时间：
2019-12-03
影响因子：
6.9
通讯作者：
Borlongan, Cesar V.
中科院分区：
文献类型：
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作者：
Lee, Jea-Young;Castelli, Vanessa;Borlongan, Cesar V.
认识到中风的病理进展与异常免疫反应密切相关，特别是外周白细胞（即T细胞）的激活，我们假设找到一种旨在抑制神经抗原特异性T细胞并阻断细胞毒性单核细胞和巨噬细胞的治疗方法可能会对中风产生治疗效果。我们之前报道过，皮下注射部分MHC II类构建体通过在中枢神经系统中促进保护性M2巨噬细胞/小胶质细胞表型以及在外周逆转中风相关的脾脏萎缩，从而促进中风小鼠的行为和组织学效应。在此，我们使用成年Sprague - Dawley大鼠作为第二种动物，使其暴露于大脑中动脉闭塞中风模型，并观察到一种名为DRmQ的小鼠部分MHC II类构建体具有类似的治疗效果，表现为中风诱导的运动缺陷、梗死、梗死周围细胞丢失和神经炎症减少。更重要的是，我们进一步提供了在脾脏水平炎症外周隔离的证据，其特征是中风诱导的脾脏重量减轻以及TNF - 和IL - 6上调的减弱。总之，这些结果满足了中风治疗学术产业圆桌会议在第二种动物中测试一种新型治疗方法的标准，并支持使用部分MHC II类构建体作为一种中风治疗方法，旨在隔离中枢和外周炎症反应，以延缓甚至阻止加剧中风继发性细胞死亡的神经炎症。
Recognizing that the pathologic progression of stroke is closely associated with aberrant immune responses, in particular the activation of peripheral leukocytes, namely T cells, we hypothesized that finding a treatment designed to inhibit neuroantigen-specific T cells and block cytotoxic monocytes and macrophages may render therapeutic effects in stroke. We previously reported that subcutaneous administration of partial MHC class II constructs promote behavioral and histological effects in stroke mice by centrally promoting a protective M2 macrophage/microglia phenotype in the CNS and peripherally reversing stroke-associated splenic atrophy. Here, we employed a second species using adult Sprague-Dawley rats exposed to the middle cerebral artery occlusion stroke model and observed similar therapeutic effects with a mouse partial MHC class II construct called DRmQ, as evidenced by reductions in stroke-induced motor deficits, infarcts, and peri-infarct cell loss and neuroinflammation. More importantly, we offered further evidence of peripheral sequestration of inflammation at the level of the spleen, which was characterized by attenuation of stroke-induced spleen weight reduction and TNF- and IL-6 upregulation. Collectively, these results satisfy the Stroke Therapy Academic Industry Roundtable criteria of testing a novel therapeutic in a second species and support the use of partial MHC class II constructs as a stroke therapeutic designed to sequester both central and peripheral inflammation responses in an effort to retard, or even halt, the neuroinflammation that exacerbates the secondary cell death in stroke.