Experimental Therapeutics

清水先生写真
Akira Shimizu, M.D., Ph.D. Professor

To improve outcome of treatment or prevention from incurable diseases by creation and development of novel treatment and diagnoses is one of the big missions given to the Kyoto University Graduate School of Medicine and to Kyoto University Hospital. For this purpose, Kyoto University Hospital took a new strategy to convert the findings of basic medicine and biology efficiently into novel clinical trial by Institute for Advancement of Clinical and Translational Science. Department of Experimental Therapeutics is for research to discover new drugs and for support to develop clinical trials.

Research and Education

On order to collect research seeds in nation-wide scale, research proposals suitable for translation termed 3-5 years were invited and selected. Collaborating with other Centers and Institutes of Graduate School of Medicine, department of Experimental Therapeutics hosts and supports the research by the Invited Research Project Unit.
Our major subject of basic research is to analyze molecular mechanisms underlying higher order functions such as immunity. Active molecular mechanisms appear to suppress IgE class switch recombination (CSR), thereby preventing serious complications during the normal course of immune response. Analyzing Id2-deficient mice, we found that the switching efficiency of IgE is enhanced in Id2-deficient B cells. Because of the lack of the Id2 gene, increased active E2A and Pax5 proteins bind to the epsilon germline promoter and augment the expression of epsilon germline transcript (GLT). As a consequence, Id2-deficient B cells undergo CSR to IgE at a much higher frequency than wild-type B cells. On the other hand, TGF-Beta1 is known to inhibit CSR to IgE.
We also found that Id2 acts as an effector molecule involved in TGF-Beta1 signaling in activate B cells. TGF-Beta1 induces Id2 expression and inhibits IgE CSR. In summary, the TGF-Beta1-Id2 pathway is required to keep the IgE concentration low in the serum, Thus, Id2 might act as a safeguard molecule to prevent harmful effects during the Th2-type immune reaction.
Recently, we found that CD4 T cells differentiate into CD8aaT cells in a manner depending on signals of TGF-b1, retinoic acids and IL-2. These cells may have regulatory role in some kinds of immune reaction, as shown in Runx3-deficient mice. These cells will belong to a new type of helper T cells.
These knowledge are important to understand control mechanisms of lymphocyte activation, and application of these results to the development of a novel treatment of allergy and of a novel method to regulate immune reaction seems to be promising. In addition to these, research on the molecule mechanism for the polarity formation of lymphocytes and the micro-environment formation at the place of immunoreaction is also ongoing.

英語_図11. Actual achievement of clinical trials

日本語_英語_図22. Id2 deficient mouse shows hyper-IgE phenotype. (A, B)

Frozen sections of mice immunized by sheep red blood cells are observed under fluorescence microscope. B lymphocytes, IgEs, and germinal center cells are stained blue, red and green respectively (A). Most of B lymphocytes of Id2 deficient mouse passively attach IgE via low affinity receptors reflecting a high IgE concentration in the serum, and cells after IgE CSR (atrined by all the three colors) are seen in some of the germinal centers of Id2 deficient mouse (B).Schematic Representation of CD8aaT cell differentiation. (C)

Publications

1. Essential role of Id2 in negative regulation of IgE class switching. Sugai, M., Gonda, H., Kusunoki, T., Katakai, T., Yokota, Y. and Shimizu, A. Nature Immunol. 4, 25-30 (2003)
2. The balance between Pax5 and Id2 activities is the key to AID gene expression. Gonda, H., Sugai, M., Nambu, Y., Katakai, T., Agata, Y., Mori, KJ., Yokota, Y. and Shimizu, A. J. Exp. Med. 198, 1427-1437 (2003)
3. Transcription-coupled events associating with immunoglobulin switch region chromatin. Nambu, Y., Sugai, M., Gonda, H., Lee, CG., Katakai, T., Agata, Y., Yokota, Y. and Shimizu, A. Science. 302, 2137-2140 (2003)
4. Lymph node fibroblastic reticular cells construct the stromal reticulum via contact with lymphocytes. Katakai, T., Hara, T., Sugai, M., Gonda, H. and Shimizu, A. J. Exp. Med. 200, 783-795 (2003).
5. In situ differentiation of CD8 alpha alpha T cells from CD4 T cells in peripheral lymphoid tissues. Nambu, Y., Hayashi, T., Jang, K. J., Aoki, K., Mano, H., Nakano, K., Osato, M., Takahashi, K., Itoh, K., Teramukai, S., Komori, T., Fujita, J., Ito, Y., Shimizu, A. and Sugai, M. Sci. Rep. 2, 642 (2012)

Diagnostic Pathology

Department of Experimental Therapeutics,
Institute for Advancement of Clinical and Translational Science,
Kyoto University Hospital

Professor:Akira Shimizu
Senior lecturer:Manabu Sugai
Lecturer (Program-specific):Takafumi Ikeda
Assistant professor:Tatsuya Ito
Assistant professor:Hiroi Kasai
Assistant professor (Program-specific):Kayoko Endo
TEL : +81-75-751-4749
FAX : +81-75-751-4731
e-mail : trc_pg@kuhp.kyoto-u.ac.jp