A novel HLA-DRα1-MOG-35-55 construct treats experimental stroke
A novel HLA-DRα1-MOG-35-55 construct treats experimental stroke
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DOI：
10.1007/s11011-013-9440-0
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发表时间：
2014-03-01
影响因子：
3.6
通讯作者：
Offner, Halina
中科院分区：
文献类型：
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作者：
Benedek, Gil;Zhu, Wenbin;Offner, Halina
诱导大脑中动脉闭塞（MCAO）后，化学吸引白细胞进入大脑增加了病变大小和疾病结局。我们以前的研究表明，部分MHC II类结构可以逆转这一过程。然而，pMHC对人类中风的潜在应用受到需要将受体MHC II类与pMHC构建体的β 1结构域快速匹配的限制。我们设计了一种新的重组蛋白，其包含与MOG-35-55肽连接的HLA-DR α 1结构域，但缺乏在pMHC中发现的β 1结构域，并在人源化DR 2小鼠中再灌注4小时后治疗MCAO。再灌注96小时后定量CT体积，并评价外周和CNS的免疫细胞的CD 74和其他细胞表面、细胞因子和途径标志物的表达。这项研究表明，每日4次DR α 1-MOG-35-55治疗可使皮质、纹状体和半球的梗死面积减少40%，抑制活化的CD 11b（+）CD 45（高）细胞从外周向脑的迁移，并逆转脾萎缩。此外，DR α 1-MOG-35-55与单核细胞上的CD 74结合并阻断巨噬细胞迁移抑制因子（MIF）的结合和下游信号传导，所述巨噬细胞迁移抑制因子（MIF）可能在梗死发展中起关键作用。新的DR α 1-MOG-35-55构建体在实验性中风中具有高度治疗性，并且可以在中风发作后至少4小时给予所有患者，而不需要组织分型，这是由于DR α 1在人类中的普遍表达。
Chemoattraction of leukocytes into the brain after induction of middle cerebral artery occlusion (MCAO) increases the lesion size and worsens disease outcome. Our previous studies demonstrated that partial MHC class II constructs can reverse this process. However, the potential application of pMHC to human stroke is limited by the need to rapidly match recipient MHC class II with the beta 1 domain of the pMHC construct. We designed a novel recombinant protein comprised of the HLA-DR alpha 1 domain linked to MOG-35-55 peptide but lacking the beta 1 domain found in pMHC and treated MCAO after 4 h reperfusion in humanized DR2 mice. Infarct volumes were quantified after 96 h reperfusion and immune cells from the periphery and CNS were evaluated for expression of CD74 and other cell surface, cytokine and pathway markers. This study demonstrates that four daily treatments with DR alpha 1-MOG-35-55 reduced infarct size by 40 % in the cortex, striatum and hemisphere, inhibited the migration of activated CD11b(+)CD45(high) cells from the periphery to the brain and reversed splenic atrophy. Furthermore, DR alpha 1-MOG-35-55 bound to CD74 on monocytes and blocked both binding and downstream signaling of macrophage migration inhibition factor (MIF) that may play a key role in infarct development. The novel DR alpha 1-MOG-35-55 construct is highly therapeutic in experimental stroke and could be given to all patients at least 4 h after stroke onset without the need for tissue typing due to universal expression of DR alpha 1 in humans.