Molecular Mechanisms and Intervention of Immunological Diseases.

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，并确定这些发现如何应用于治疗疾病或改善人类健康。过去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细胞和非淋巴细胞谱系。胚胎干细胞技术的最新进展使我们能够产生大量的各种转基因和基因靶向小鼠。一些基因靶向小鼠为我们提供了一个有用的工具，评估免疫疾病作为人类模型。对内源性抗原和外源性抗原的免疫应答触发疾病的发作，如变态反应、自身免疫性疾病和严重的慢性炎症，这也是事实。 ...更多信息 疾病超过10%的日本总人口患有对环境过敏原的过敏，如雪松花粉和屋尘螨。然而，如何通过免疫策略来防治变态反应性疾病，仍是一个亟待解决的问题。许多变态反应患者和医生容易倾向于使用非特异性炎症药物如糖皮质激素来治疗变态反应性疾病，本研究项目的目的是阐明免疫紊乱的分子机制和干预措施。为了完成我们的目标和任务，我们成立了四个主要的研究小组，每个小组都对以下项目进行了研究。这些机制包括：早期淋巴发育中的库选择机制、免疫多样性和免疫耐受机制及其破坏机制、通过抗原和细胞因子受体及共刺激分子介导的信号通路及其异常机制、免疫性疾病的干预机制。在四年的任期内，在免疫学领域和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）已经建立了监测来自骨髓干细胞的淋巴系发育的实验系统，并阐明了B和T细胞祖细胞来源于多能干细胞，而不是来源于普通淋巴祖细胞。(2)Toll样受体（TLR）家族的新分子（TLR 6至11、RP 105等）和相关信号分子（MyD 88、MD-1、MD-2等）通过产生基因敲除小鼠被鉴定并阐明了它们的功能。结果显示TLR在保护宿主免受细菌感染方面起关键作用。(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，与细胞因子受体偶联的新型信号分子如STAM、JAB/SSI-1、CIS、Smad 6/7，并通过产生基因靶向阐明了分子中每个成员的功能。细胞因子信号分子和TGF-β受体信号分子之间的相互作用被发现。(4)阐明了人和小鼠中Btk在B细胞发育中的作用，并鉴定了每个日本XLA患者中的Btk突变。本研究旨在揭示IL-5在变态反应和黏膜免疫中的作用，并利用豚鼠过敏性哮喘模型评价抗IL-5单克隆抗体预防过敏性哮喘的可行性。少

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