THE MOLECULAR MECHANISMS OF IMMUNE RESPONSE AND INTERACTION OF THE IMMUNE AND NERVOUS SYSTEMS IN FOOD ALLERGY

食物过敏中免疫反应的分子机制以及免疫和神经系统的相互作用

• 批准号: 10306008
• 负责人: KAMINOGAWA Shuichi
• 金额: $ 23.74万
• 依托单位: THE UNIVERSITY OF TOKYO
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A).
• 财政年份: 1998
• 资助国家: 日本
• 起止时间: 1998 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-10306008/
• 关键词: food allergy; TCR antagonism; altered peptide ligand; intestinal immune system; cytokine; neural cell; nitric oxide; apoptosis; アナログペプチド; 脳細胞; T細胞; 細胞死; p53; IgE; 神経幹細胞

1. The response of T cells from transgenic(Tg)mice expressing T-cell receptor(TCR)specific for residues 323-339 of ovalbumin(OVA323-339)could be classified into at least four types according to the pattern of cytokine secretion and induction of antibody production, when a panel of 40 amino-acid substituted analogs of OVA323-339 was used as stimulations. The similarly classified response could be elicited by changing the dose of OVA323-339 used for stimulants. We also found peptides with ability to inhibit the T-cell response to OVA323-339 among the panel of analog peptides. Intraperitoneal administration of the inhibitory peptide could suppress food-allergic reaction in an animal model. 2. The response of the intestinal immune system to orally administrated allergen was examined using the OVA-specific TCR-Tg mice. Peyer's patch cells from OVA-fed TCR-Tg mice secreted IFN-gamma and IL-5 in response to antigen stimulation, and intraepithelial lymphocytes secreted IFN-gamma. The response of splenic CD4 T cells was diminished, indicative of oral tolerance. Ca_<2+> mobilization after TCR-ligation was impaired in these tolerant T cells. OVA feeding induced apoptosis of thymocytes and CD4 T cells in lymph nodes, and oral tolerance was partly abrogated in p53-deficient mice. In addition, the differences in antigen presentation functions between splenic cells and Peyer's patch cells were clarified. 3. The effect of inflammatory cytokines on neural cell response was estimated by an in vitro culture system using embryonic mouse brain cells. As a result, both IL-6 family cytokines and TGF-beta family cytokines induced glial differentiation of neural progenitor cells. In addition, nitric oxide produced by inflammatory type NOS triggered apoptosis of neural cells in a p53-dependent manner. These findings clearly demonstrate the interaction between inflammatory system and nervous system.

1.当使用一组40个氨基酸取代的OVA 323 - 339类似物作为刺激物时，来自表达特异于卵清蛋白残基323-339（OVA 323 -339）的T细胞受体（TCR）的转基因（Tg）小鼠的T细胞的反应可以根据细胞因子分泌和诱导抗体产生的模式被分为至少四种类型。通过改变用于刺激剂的OVA 323 -339的剂量，可以引起类似分类的反应。我们还在一组类似物肽中发现了具有抑制对OVA 323 -339的T细胞应答的能力的肽。在动物模型中，腹膜内给予抑制肽可以抑制食物过敏反应。2.使用OVA特异性TCR-Tg小鼠检查肠道免疫系统对口服给予的变应原的应答。来自OVA喂养的TCR-Tg小鼠的派伊尔斑细胞响应于抗原刺激而分泌IFN-γ和IL-5，并且上皮内淋巴细胞分泌IFN-γ。脾CD 4 T细胞的反应减弱，表明口服耐受。TCR结扎后，这些耐受性T细胞的Ca_（2+）动员受到损害。OVA喂养诱导胸腺细胞和淋巴结中的CD 4 T细胞凋亡，并且p53缺陷小鼠的口服耐受性部分被废除。此外，还阐明了脾细胞和派伊尔集合淋巴结细胞在抗原提呈功能上的差异。3.通过使用胚胎小鼠脑细胞的体外培养系统来评估炎性细胞因子对神经细胞反应的影响。结果，IL-6家族细胞因子和TGF-β家族细胞因子均诱导神经祖细胞的胶质分化。此外，炎症型NOS产生的一氧化氮以p53依赖的方式触发神经细胞凋亡。这些发现清楚地表明了炎症系统和神经系统之间的相互作用。

项目成果

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