DRα1-MOG-35-55 Reduces Permanent Ischemic Brain Injury.
DRα1-MOG-35-55 Reduces Permanent Ischemic Brain Injury.
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DOI：
10.1007/s12975-016-0514-2
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发表时间：
2017-06
影响因子：
6.9
通讯作者：
Gao Y
中科院分区：
文献类型：
--
作者：
Wang J;Ye Q;Xu J;Benedek G;Zhang H;Yang Y;Liu H;Meza-Romero R;Vandenbark AA;Offner H;Gao Y
中风诱导灾难性的免疫反应，涉及外周白细胞，特别是T细胞的整体激活。DR α1-MOG-35-55（DRα1-MOG-35-55）是一种主要组织相容性复合物II（MHC II）结构域，可抑制神经抗原特异性T细胞，并阻断细胞因子/趋化因子巨噬细胞迁移抑制因子（MIF）与单核细胞和巨噬细胞上的CD 74受体的结合。在此，我们评估了DRα1-MOG-35-55在永久性远端大脑中动脉闭塞（dMCAO）小鼠模型中的治疗作用。在缺血发作后4小时开始皮下注射给予WT C57 BL/6小鼠DRα1-MOG-35-55，随后每日注射3次。我们证明DRα1-MOG-35-55后处理显著减少脑梗死体积，改善功能结局，并抑制dMCAO后96 h缺血脑中CD 4+和CD 8 + T细胞的积聚和促炎细胞因子的表达。此外，DRα1-MOG-35-55处理使缺血性脑中的小胶质细胞/巨噬细胞转变为有益的M2表型，而不改变其在脑或血液中的总数。本研究首次证明了DRα1-MOG-35-55构建体在C57 BL/6小鼠中跨越MHC II类屏障的dMCAO中的治疗功效。这种MHC非依赖性效应消除了组织分型的需要，因此将大大加快DRα1-MOG-35-55在人类卒中受试者中的治疗。综上所述，我们的研究结果表明，DRα1-MOG-35-55治疗可能通过调节脑和外周的卒中后免疫反应来减轻缺血性脑损伤。
Stroke induces a catastrophic immune response that involves the global activation of peripheral leukocytes, especially T cells. The HLA-DRα1 domain linked to MOG-35-55 peptide (DRα1-MOG-35-55) is a partial major histocompatibility complex II (MHC II) construct which can inhibit neuroantigen-specific T cells and block binding of the cytokine/chemokine macrophage migration inhibitory factor (MIF) to its CD74 receptor on monocytes and macrophages. Here, we evaluated the therapeutic effect of DRα1-MOG-35-55 in a mouse model of permanent distal middle cerebral artery occlusion (dMCAO). DRα1-MOG-35-55 was administered to WT C57BL/6 mice by subcutaneous injection starting 4h after the onset of ischemia followed by 3 daily injections. We demonstrated that DRα1-MOG-35-55 post-treatment significantly reduced brain infarct volume, improved functional outcomes and inhibited the accumulation of CD4+ and CD8+ T cells and expression of pro-inflammatory cytokines in the ischemic brain 96h after dMCAO. In addition, DRα1-MOG-35-55 treatment shifted microglia/macrophages in the ischemic brain to a beneficial M2 phenotype without changing their total numbers in the brain or blood. This study demonstrates for the first time the therapeutic efficacy of the DRα1-MOG-35-55 construct in dMCAO across MHC class II barriers in C57BL/6 mice. This MHC independent effect obviates the need for tissue typing and will thus greatly expedite treatment with DRα1-MOG-35-55 in human stroke subjects. Taken together, our findings suggest that DRα1-MOG-35-55 treatment may reduce ischemic brain injury by regulating post-stroke immune responses in the brain and the periphery.