Immunomodulation and adult neurogenesis after stroke

中风后的免疫调节和成人神经发生

• 批准号: 21790836
• 负责人: ISHIBASHI Satoru
• 金额: $ 2.75万
• 依托单位: Tokyo Medical and Dental University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21790836/
• 关键词: 脳血管障害; 制御性T細胞; E-セレクチン; 神経新生; 神経幹細胞; 動物モデル; 再生医療; 神経保護; 炎症; リンパ球

Neuroblasts in the subventricular zone proliferate markedly after stroke, and migrate to the site of injury along with blood vessels. However, a large fraction of stroke-generated neuroblasts die shortly after being born, because of local inflammation.E-selectin is specifically expressed on endothelial cells, but only when the endothelium activates. Since endothelial activation occurs after stroke, E-selectin can serve as an immunologic tolerization antigen that can focus immunomodulation to regions of the vascular tree. Intranasal instillation of recombinant E-selectin will induce mucosal tolerance to that antigen with the generation of E-selectin-specific regulatory T cells (Tregs). Tregs may protect newly-generated neuroblasts from ischemic damage through'bystander suppression' in which immunomodulatory cytokines such as TGF-β and IL-10 are released locally. In this series of experiments, we have shown that after E-selectin tolerization in permanent middle cerebral artery occlusion (pMCAO) rats Tregs transmigrate to the peri-infarct region of ischemic brain, TNF expression in the local neurovascular niche is reduced, and the survival of newly generated neuroblasts or neurons in the peri-infarct region is increased. Under these conditions, an improvement in sensorimotor function after pMCAO also occurs.E-selectin-specific Tregs can modulate the efficacy of adult neurogenesis after ischemia and promote repair after brain injury.

中风后脑室下区的神经母细胞显着增殖，并随血管迁移至损伤部位。然而，由于局部炎症，大部分中风产生的神经母细胞在出生后不久就死亡。内皮细胞，但仅当内皮细胞激活时，由于中风后发生内皮细胞激活，E-选择素可以作为免疫耐受抗原，将免疫调节集中于内皮细胞区域。重组E-选择素的鼻内滴注将诱导粘膜对该抗原的耐受，并产生E-选择素特异性调节性T细胞（Treg），可以通过“旁观者抑制”保护新生的神经母细胞免受缺血性损伤。在这一系列实验中，我们已经证明，E-选择素永久耐受后，局部释放免疫调节细胞因子，例如 TGF-β 和 IL-10。大脑中动脉闭塞（pMCAO）大鼠Treg细胞迁移至缺血脑梗死周围区域，局部神经血管微环境中TNF表达减少，梗死周围区域新生神经母细胞或神经元的存活增加。在条件下，pMCAO 后感觉运动功能也会出现改善。E-选择素特异性 Tregs 可以调节缺血后成体神经发生的功效，并促进脑损伤后的修复。

项目成果

脳血管障害治療の次のブレークスルーを目指して:Immunomodulation by inducing tolerance to E-selectin and adult neurogenesis after stroke

瞄准脑血管疾病治疗的下一个突破：通过诱导E-选择素耐受和中风后成人神经发生进行免疫调节

• 发表时间: 2010
• 作者: 石橋哲

ラット中大脳動脈閉塞モデルを使用した制御性T細胞誘導が脳梗塞後のneurovascular nicheに与える効果の検討

利用大鼠大脑中动脉闭塞模型研究调节性T细胞诱导对脑梗死后神经血管微环境的影响

• 发表时间: 2009
• 作者: 石橋哲;John M.Hallenbeck; 水澤英洋
• 通讯作者: 水澤英洋

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