ELUCIDATION OF THE MOLECULAR MECHANISMS OF THE INTESTINAL IMMUNE RESPONSE TO FOOD PROTEIN ANTIGENS

阐明肠道对食物蛋白抗原免疫反应的分子机制

• 批准号: 12660110
• 负责人: HACHIMURA Satoshi
• 金额: $ 2.11万
• 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 (C)
• 财政年份: 2000
• 资助国家: 日本
• 起止时间: 2000 至 2001
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12660110/
• 关键词: intestinal immune response; Peyer's patch; oral tolerance; T cell; signal transduction; dendritic cell; interleukin 5; interleukin 6

1. Interlaken (IL) -5 and IL-6 secretion of Peyer's patch cells. (1) It was demonstrated that PP dendritic cells (DCs), particularly CD11b^+ DCs produced higher levels of IL-6 compared to SP DCs. (2) We found that naive CD4 T cells had a high capacity to secrete IL-6. (3) We found that IL-2R^+ CD3^-B220^- non T, non-B cells isolated from PP cells secreted IL-5 in response to IL-2. These IL-2R^+ cells did not belong to previously known IL-5 producing cells, such as T cells, mast cells, NK cells or eosinophils. Deoletion of IL-2R^+CD3^-B220^- cells from PP cells resulted in reduced IL-5 production.2. Signal transduction pathways in orally tolerant CD4 T cells induced in ovalbumin-specific T cell receptor (TCR) transgenic mice fed with ovalbumin was examined. In these T cells (1) impaired phosphorylation of TCR-ζ, ZAP-70, LAT (2) impaired calcium responses and decreased NFAT nuclear translocation, (3) normal activation of ERK and SAPK (MAPK pathway), and (4) impaired degradation of p27^<kip1> induced by IL-2 stimulation was demonstrated. Thus, hyporesponsiveness in the orally tolerant CD4 T cell appears to be associated with two defects : impaired TCR-induced activation of the calcium pathway, and impaired p27 ^<kip1> degradation induced by stimulation thorough IL-2R.

1.派尔集合淋巴结细胞分泌因特拉肯（IL）-5和IL-6。(1)研究表明，PP树突状细胞（DC），特别是CD 11b ^+ DC，比SP DC产生更高水平的IL-6。(2)我们发现初始CD 4 T细胞具有高的分泌IL-6的能力。(3)我们发现，从PP细胞中分离的IL-2 R ^+ CD 3 ^-B220^-非T、非B细胞对IL-2产生应答，分泌IL-5。这些IL-2 R ^+细胞不属于先前已知的产生IL-5的细胞，如T细胞、肥大细胞、NK细胞或嗜酸性粒细胞。从PP细胞中去除IL-2 R ^+ CD 3 ^-B220^-细胞导致IL-5产生减少。检测了用卵清蛋白喂养的卵清蛋白特异性T细胞受体（TCR）转基因小鼠中诱导的口服耐受性CD 4 T细胞的信号转导途径。在这些T细胞中，证实了（1）TCR-γ、ZAP-70、LAT的磷酸化受损，（2）钙应答受损和NFAT核转位减少，（3）ERK和SAPK（MAPK途径）的正常激活，和（4）<kip1>由IL-2刺激诱导的p27 β的降解受损。因此，口服耐受性CD 4 T细胞中的低反应性似乎与两个缺陷相关：TCR诱导的钙通路活化受损，以及<kip1>通过IL-2 R刺激诱导的p27 β降解受损。

项目成果

M.Hashiguchi, et al.: "Th2 polarization enhanced by oral administration of higher doses of antigen"Cytotechnology. 33. 237-245 (2000)

M.Hashiguchi 等人：“口服较高剂量抗原可增强 Th2 极化”细胞技术。

W.Ise, et al.: "Naive CD4^+ T cells exhibit distinct expression patterns of cytokines and cell surface molecules on their primary responses to varying doses of antigen"J. Immunol.. (in perss). (2002)

W.Ise 等人：“幼稚 CD4^T 细胞在对不同剂量抗原的初次反应中表现出细胞因子和细胞表面分子的不同表达模式”J.

A.Sato, et al.: "The role dendritic cells play in the cytokine response in Peyer's patches"Animal Cell Technology : Basic & Applied Aspects. 12. 213-217 (2001)

A.Sato 等人：“树突状细胞在派尔氏淋巴结细胞因子反应中所发挥的作用”动物细胞技术：基础

S.Nagafuchi, et al.: "Dietary nucleotides increase the proportion of a TCRγδ^+ subset of intraepithelial lymphocytes (IEL) and IL-7 production by intestinal epithelial cells (IEC) : Implications for modification of cellular and molecular cross-talk betwee

S.Nagafuchi 等人：“膳食核苷酸增加了上皮内淋巴细胞 (IEL) 的 TCRγδ^+ 子集的比例以及肠上皮细胞 (IEC) 产生的 IL-7：对改变细胞和分子之间的串扰的影响

Y.Ueda, et al.: "Apoptosis of antigen-specific T cell induced by oral administration of antigen : comparison of intestinal and non-intestinal immune organs"Biosci. Biotechol. Biochem.. 65. 1170-1174 (2001)

Y.Ueda等人：“口服抗原诱导的抗原特异性T细胞凋亡：肠道和非肠道免疫器官的比较”Biosci。