Molecular Mechanisms and Intervention of Immunological Diseases.

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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