Pathogenesis and regulation mechanisms for Th1- and Th2-dependent allergic airway inflammation

Th1和Th2依赖性过敏性气道炎症的发病机制和调控机制

• 批准号: 18604001
• 负责人: NISHIMURA Takashi
• 金额: $ 2.5万
• 依托单位: Hokkaido University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18604001/
• 关键词: Allergy-Asthma; Gene; Cell-Tissue; Animal; Immunology; アレルギー・ぜんそく; 気道アレルギー; Th2; CpG; サイトカイン; DNAアレイ; 免疫バランス; 乳酸菌; Th1

To overcome various immune diseases induced by disruption of type1/type2 immune balance, we have established Th1- or Th2-dependent immune diseases models. In the present project, we established allergic airway inflammation mouse models by adoptive transfer of antigen-specific Th1 or Th2 cells followed by the antigen inhalation and investigated precise cellular regulation and molecular mechanisms in the pathogenesis. In the present models, transfer of Th1 cells induced fatal airway hyperresponsiveness (AHR) associated with severe neutrophilia, whereas the cased of Th2 cells caused eosinophilia in the lung. Compared to the Th2-transferred model, mRNA expression levels of MUC5AC and Gob5, related to mucus hypersecretion in airway epithelium, were extremely lower in the Th1 -transferred model. Thus, it was demonstrated that the Th1-induced AHR was independent on such mucus hypersecretion, which was essential for elevation of AHR in Th2-mediated asthma. In the Th2-transferred model, we foun … More d that in vivo injection of TLR9 ligand, CpG remarkably suppressed the symptoms by blocking of Th2-cell migration into lung. To investigate the mechanism, we used IFN-γ knockout mice and neutralizing antibodies against type I cytokines such as IFN-α, β, and IL-12. As the results, IFN-α, β, and IL-12, but not IFN-γ, were required for the inhibitory effect of CpG on Th2-cell migration. These findings were highly valued for elucidation of the suppression mechanism mediated by down-regulation of Th2-cell migration into lung even at effector phase, suggesting that CpG would be expected as a tool for clinical application in Th2-dependent asthma.Furthermore, we evaluated inhibitory effects of lactic acid bacterium (LAB), which easily activate type1 immunity, on Th2-dependent asthma. As the results, it was suggested that oral intake of LAB may have preventative effects on the allergic inflammation at induction phase rather than therapeutic effects at effector phase. The present findings will contribute to elucidation of the pathogenesis and development of the proper regulation in allergic airway inflammation. Less

为了克服1型/2型免疫平衡破坏引起的各种免疫疾病，我们建立了Th1或Th2依赖性免疫疾病模型。在本项目中，我们通过过继转移抗原特异性Th1或Th2来建立过敏性气道炎症小鼠模型。在目前的模型中，Th1 细胞的转移诱导了与严重中性粒细胞增多相关的致命性气道高反应性（AHR），并研究了发病机制中的精确细胞调节和分子机制。与Th2转移模型相比，Th2细胞引起肺部嗜酸性粒细胞增多，与气道上皮粘液过度分泌相关的MUC5AC和Gob5的mRNA表达水平在Th1转移模型中极低。诱导的 AHR 独立于粘液过度分泌，这对于 Th2 介导的哮喘中 AHR 的升高至关重要。在 Th2 转移模型中，我们发现……更多d 体内注射 TLR9 配体 CpG 通过阻止 Th2 细胞迁移到肺部来显着抑制症状。为了研究其机制，我们使用了 IFN-γ 敲除小鼠和针对 I 型细胞因子（如 IFN-α、β）的中和抗体。结果表明，CpG 对 Th2 细胞迁移的抑制作用需要 IFN-α、β 和 IL-12，而不是 IFN-γ。阐明了即使在效应期，Th2细胞迁移到肺的下调介导的抑制机制，表明CpG有望作为Th2依赖性哮喘临床应用的工具。此外，我们评估了乳酸菌的抑制作用(LAB)，很容易激活1型免疫，对Th2依赖性哮喘。结果表明，口服LAB可能对诱导期的过敏性炎症具有预防作用，而不是对效应器的治疗作用。目前的研究结果将有助于阐明过敏性气道炎症的发病机制和适当调节的发展。

项目成果

Generating tumor- or OK432-specific Th1 cells Applicable to clinical trial of Th1 cell therapy

产生肿瘤或OK432特异性Th1细胞 适用于Th1细胞疗法的临床试验

• 发表时间: 2007
• 作者: Takayuki Ohkuri;et. al.
• 通讯作者: et. al.

IL-17-producing gd T cells infiltrated into tumor site promote angiogenesis and tumor progression

浸润肿瘤部位的产生 IL-17 的 gd T 细胞促进血管生成和肿瘤进展

• 发表时间: 2007
• 作者: Daiko Wakita;et. al.
• 通讯作者: et. al.

NKT cells from IL-4-deficient mice are defective in early IFN-γ production in response to α-galactosylceramide

IL-4 缺陷小鼠的 NKT 细胞在响应 α-半乳糖神经酰胺的早期 IFN-γ 产生中存在缺陷

• 发表时间: 2007
• 期刊: Cancer Science 98
• 作者: Daisuke Noguchi;Yuji Togashi
• 通讯作者: Yuji Togashi

医学のあゆみ

医学史

• 发表时间: 2022
• 作者: 藤田陽子;野田岳志
• 通讯作者: 野田岳志

新規自己免疫性大腸炎モデルの確立:IL-6依存的spontaneous proliferationによるTc17エフェクター細胞の誘導

新型自身免疫性结肠炎模型的建立：IL-6依赖性自发增殖诱导Tc17效应细胞

• 发表时间: 2007
• 作者: Hidemitsu Kitamura;et. al.;北村 秀光;但馬 正樹
• 通讯作者: 但馬 正樹