Molecular Mechanisms and Intervention of Immunological Diseases.

免疫疾病的分子机制和干预。

• 批准号: 08282101
• 负责人: TAKATSU Kiyoshi
• 金额: $ 38.46万
• 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 on Priority Areas
• 财政年份: 1996
• 资助国家: 日本
• 起止时间: 1996 至 2000
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-08282101/
• 关键词: Repertoire selection; Antigen receptor; Immunodiversity; Tyrosine kinase; Inflammation; Immunological disorders; Signal transduction; IL-5; 免疫職別の多型性; 免疫職別の多様性; 免疫制御; 免疫寛容; MHCと抗原ペプチド; シグナル伝達; 抗原レセプター; サイトカイン; 自己免疫病; アレルギー; 免疫病の分子機構; 自己認

Immunological research has been a dual challenge for immunologists and physicians : discovering regulatory mechanism of the complex immune system, and determining how these discoveries may be applied to cure diseases or improve the health mankind. For the last 25 years, tremendous progress has been made in immunological research and clarified components involved in the immune regulation, including genes for antigen receptor and cytokine and its receptor, molecules for MHC gene products and costimulatory signals, and cells in lymphoid and non-lymphoid lineage. Recent advances on embryonic stem cell technology have enabled us to generate numerous numbers of various transgenic and gene-targeted mice. Some of gene-targeted mice provide us a useful tool for evaluating immunological disorders as human models. It is also true that the immune response to endogenous antigen as well as exogenous one trigger the onset of disease such as allergy, autoimmune disease, and severe chronic inflammatory … More disease. More than 10% of total Japanese population suffer from some allergy against environmental allergen such as cedar pollen and house-dust mite. However, it is still remained suffering how we prevent and cure from allergic diseases by immunological maneuver. Many of allergy patients and physicians easily tend to use non-specific inflammatory drugs such as glucocorticoid to treat allergic diseases.Aims of this research project supported by Grant-in-Aid for core research was to clarify molecular mechanisms and intervention of immunological disorders. We built up four major research groups to accomplish our aims and task each one of which investigated the following project. These are repertoire selection mechanism in early lymphoid development, mechanism of immunological diversity and tolerance and its break-down, mechanism of signaling pathway and its abnormality through antigen and cytokine receptor and costimulatory molecules, and intervention of immunological diseases. For four-year term, a number of exciting results were published in the international journals related in immunology field and in other related fields as well. For example, (1) experimental system to monitor for lymphoid-lineage development from bone marrow stem cells has been established and clarified that B and T cell progenitors are derived from pluripotent stem cells, but not from common lymphoid progenitors. (2) Novel molecules of Toll-like receptor (TLR) family (TLR6 through 11, RP105, and others) and related signaling molecules (MyD88, MD-1, MD-2, and others) were idnetified and their functions were clarified by generating gene knocked-out mice. Results revealed that TLR plays a critical role in protecting host against bacterial infection. (3) Novel signaling molecules coupled with BCR such as BLNK/BASH, with TCR such as pre-TCRα, and with cytokine receptor such as STAM, JAB/SSI-1, CIS, Smad6/7 were cloned and function of each member of molecules were clarified by generating gene-targeting. Intriguing molecular interaction between cytokine signaling molecule and TGF-β receptor signaling molecule was discovered. (4) Role of Btk in human and mouse in B cell development were clarified and mutations of Btk in each of Japanese XLA patients were identified. Role of IL-5 in allergy and mucosal immunology was disclosed and feasibility of anti-IL-5 mAb in preventing allergic asthma was evaluated using allergic guinea pig model. Less

免疫学研究一直是免疫学家和医生面临的双重挑战：发现复杂免疫系统的调节机制，并确定如何将这些发现应用于治疗疾病或改善人类健康。近25年来，免疫学研究取得了巨大进展，阐明了参与免疫调节的成分，包括抗原受体和细胞因子及其受体的基因、MHC基因产物和共刺激信号的分子、以及淋巴和非淋巴谱系的细胞。胚胎干细胞技术的最新进展使我们能够培育出大量不同的转基因和基因靶向小鼠。一些基因靶向小鼠为我们提供了作为人类模型评估免疫疾病的有用工具。确实，对内源性抗原和外源性抗原的免疫反应会引发过敏、自身免疫性疾病和严重慢性炎症等疾病。日本总人口的 10% 以上对雪松花粉和屋尘螨等环境过敏原过敏。然而，如何通过免疫手段防治过敏性疾病仍是一个难题。许多过敏患者和医生很容易倾向于使用糖皮质激素等非特异性炎症药物来治疗过敏性疾病。本次核心研究项目的目的是阐明免疫紊乱的分子机制和干预措施。我们成立了四个主要研究小组来完成我们的目标和任务，每个小组都研究了以下项目。这些是早期淋巴发育的库选择机制，免疫多样性和耐受性及其分解机制，通过抗原和细胞因子受体和共刺激分子的信号通路机制及其异常，以及免疫疾病的干预。四年来，在免疫学领域及其他相关领域的国际期刊上发表了许多令人兴奋的成果。例如，（1）建立了监测骨髓干细胞淋巴谱系发育的实验系统，并阐明B和T细胞祖细胞源自多能干细胞，而不是源自普通淋巴祖细胞。 (2)通过生成基因敲除小鼠，鉴定了Toll样受体(TLR)家族的新分子(TLR6至11、RP105等)及相关信号分子(MyD88、MD-1、MD-2等)并阐明其功能。结果表明，TLR 在保护宿主免受细菌感染方面发挥着关键作用。 (3)克隆了与BCR偶联的新型信号分子如BLNK/BASH，与TCR偶联的新型信号分子如pre-TCRα，以及与细胞因子受体偶联的新型信号分子如STAM、JA​​B/SSI-1、CIS、Smad6/7，并通过生成基因靶向阐明各分子成员的功能。细胞因子信号分子和 TGF-β 受体信号分子之间有趣的分子相互作用被发现。 (4)阐明了Btk在人和小鼠B细胞发育中的作用，并鉴定了每位日本XLA患者的Btk突变。揭示了 IL-5 在过敏和粘膜免疫学中的作用，并使用过敏性豚鼠模型评估了抗 IL-5 mAb 在预防过敏性哮喘中的可行性。较少的

项目成果

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Tsukamoto, N., M.Hattori, N.Minato, et al.: "SPA-1 negatively regulates cell adhesion through GAP activity for Rap 1"J.Biol.Chem.. 274. 18463-18469 (1999)

Tsukamoto, N.、M.Hattori、N.Minato 等人：“SPA-1 通过 Rap 1 的 GAP 活性负向调节细胞粘附”J.Biol.Chem.. 274. 18463-18469 (1999)

Yoshida, T., K.Ikuta, S.Takaki, K.Takatsu, et al.: "Defective B-1 cells development and impaired immunity against Angiostrongylus cantonensis in IL-5Rα deficient mice."Immunity. 4. 483-494 (1996)

Yoshida, T.、K.Ikuta、S.Takaki、K.Takatsu 等人：“IL-5Rα 缺陷小鼠中 B-1 细胞发育缺陷和针对广州管圆线虫的免疫力受损。”免疫。 1996）