Elucidation of molecular mechanisms for the regulation of immune response by reconstruction of microenvironment and analyses of transcription factors and their networks

• Project/Area Number: 21390077
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General medical chemistry
• Research Institution: Kyoto University
• Principal Investigator: SHIMIZU Akira 京都大学, 医学(系)研究科(研究院), 教授 (00162694)
• Project Period (FY): 2009-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000); Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2011: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2010: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2009: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 分子免疫学 / 免疫制御 / 転写因子 / 遺伝子組換え / 抗体遺伝子 / 発現制御 / 免疫学 / 遺伝子 / 腸管免疫 / 制御性T細胞 / IgA / Runx / retinoic acid / TGF-β1 / 自己免疫炎症 / クラススイッチ

Research Abstract

It is essential for proper for proper progression of immune reaction that construction of specific microenvironment and harmonized function of a variety of immuno-competent cells. It is tried to elucidate molecular mechanisms of such immune reaction by reconstruction of such microenvironment in vitro and analyses of transcription factors and their networks regulated by such microenvironment.
An in vitro culture system that very efficiently induces class switching to IgA was established. It was found that Runx transcription factors are essential for IgA class switching and they act downstream of signals from retinoic acid TGF-beta1, and that Runx3 is essential for differentiation and maturation of regulatory T cells.

Research Products

• [Journal Article] Phenotypes of CCAAT/enhancer-binding protein beta deficiency : Hyperdontia and elongated coronoid process (2013)
  • Author(s): Huang, B., Takahashi, K., Sakata-Goto, T., Kiso, H., Togo, Y., Saito, K., Tsukamoto, H., Sugai, M., Akira, S., Shimizu, A., Bessho, K.
  • Journal Title: Oral Diseases Volume: 19 Pages: 144-150
  • Peer Reviewed
• [Journal Article] Evasion from accelerated blood clearance of nanocarrier named as "Lactosome" induced by excessive administration of Lactosome (2013)
  • Author(s): Hara, E., Makino, A., Kurihara, K., Sugai, M., Shimizu, A., Hara, I., Ozeki, E., Kimura, S.
  • Journal Title: Biochem. Biophys Acta-General Sub. Volume: 1830 Pages: 4046-4052
  • Peer Reviewed
• [Journal Article] Novel collagen/gelatin scaffold with sustained release of basic fibroblast growth factor : clinical trial for chronic skin ulcers (2013)
  • Author(s): Morimoto, N., Yoshimura, K., Niimi, M., Ito, T., Aya, R., Fujitaka, J., Tada, H., Teramukai, S., Murayama, T., Toyooka, C., Miura, K., Takemoto, S., Kanda, N., Kawai, K., Yokode, M., Shimizu, A., Suzuki, S.
  • Journal Title: Tissue Enginer. Part A Volume: 19 Pages: 1931-1940
  • NAID: 120005312059
  • Peer Reviewed
• [Journal Article] Phenotypes of CCAAT/enhancer-binding protein beta deficiency: Hyperdontia and elongated coronoid process. (2013)
  • Author(s): Huang, B., Takahashi, K., Sakata-Goto, T., Kiso, H., Togo, Y., Saito, K., Tsukamoto, H., Sugai, M., Akira, S., Shimizu, A. and Bessho, K.
  • Journal Title: Oral Diseases Volume: 19 Issue: 2 Pages: 144-150
  • DOI: 10.1111/j.1601-0825.2012.01963.x
  • Peer Reviewed
• [Journal Article] Evasion from accelerated blood clearance of nanocarrier named as "Lactosome" induced by excessive administration of Lactosome. (2013)
  • Author(s): Hara, E., Makino, A., Kurihara, K., Sugai, M., Shimizu, A., Hara, I., Ozeki, E. and Kimura, S.
  • Journal Title: Biochem. Biophys. Acta-General Sub. Volume: 1830 Issue: 8 Pages: 4046-4052
  • DOI: 10.1016/j.bbagen.2013.03.024
  • Peer Reviewed
• [Journal Article] Novel collagen/gelatin scaffold with sustained release of basic fibroblast growth factor: clinical trial for chronic skin ulcers. (2013)
  • Author(s): Morimoto, N., Yoshimura, K., Niimi, M., Ito, T., Aya, R., Fujitaka, J., Tada, H., Teramukai, S., Murayama, T., Toyooka, C., Miura, K., Takemoto, S., Kanda, N., Kawai, K., Yokode, M., Shimizu, A. and Suzuki, S.
  • Journal Title: Tissue Engineer. Part A Volume: 19 Issue: 17-18 Pages: 1931-1940
  • DOI: 10.1089/ten.tea.2012.0634
  • NAID: 120005312059
  • Peer Reviewed
• [Journal Article] Id2 controls chondrogenesis acting downstream of BMP signaling during maxillary morphogenesis (2012)
  • Author(s): Sakata-Goto, T., Takahashi, K., Kiso, H., Huang, B., Tsukamoto, H., Takemoto, M., Hayashi, T., Sugai, M., Nakamura, T., Yokota, Y., Shimizu, A., Slavkin, H., Bessho, K.
  • Journal Title: Bone Volume: 50 Pages: 69-78
  • Peer Reviewed
• [Journal Article] In situ differentiation of CD8aa T cells from CD4 T cells in peripheral lymphoid tissues (2012)
  • Author(s): 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., Sugai, M.
  • Journal Title: Scientific Reports Volume: 2 Pages: 642-642
  • Peer Reviewed
• [Journal Article] Id2 controls chondrogenesis acting downstream of BMP signaling during maxillary morphogenesis (2012)
  • Author(s): Sakata-Goto T
  • Journal Title: Bone Volume: 50 Issue: 1 Pages: 69-78
  • DOI: 10.1016/j.bone.2011.09.049
  • Peer Reviewed
• [Journal Article] In situ differentiation of CD8αα T cells from CD4 T cells in peripheral lymphoid tissues (2012)
  • Author(s): Nambu Y., Hayashi T., Jang KJ, Aoki K., Mano H., Nakano K., Osato M., Takabashi K., Itoh K., Teramukai S., Komon T., Fujita J., Ito Y., Shimizu
  • Journal Title: Scientific Reports Volume: 2 Issue: 1 Pages: 930-930
  • DOI: 10.1038/srep00642
  • Peer Reviewed
• [Journal Article] Runx3 is required for full activation of regulatory T cells to prevent colitis-associated tumor formation (2011)
  • Author(s): Sugai, M., Aoki, K., Osato, T., Nambu, Y., Ito, K., Taketo, M. M., Ito, Y., Shimizu, A.
  • Journal Title: J. Immunol. Volume: 186 Pages: 6515-6520
  • Peer Reviewed
• [Journal Article] Cross-priming of CD8(+) T cells in vivo by dendritic cells pulsed with autologous apoptotic leukemic cells in immunotherapy for elderly patients with acute myeloid leukemia (2011)
  • Author(s): Kitawaki, T., Kadowaki, N., Fukunaga, K., Kasai, Y., Maekawa, T., Ohmori, T., Itoh, T., Shimizu, A., Kuzushima, K., Kondo, T., Ishikawa, T., Uchiyama, T.
  • Journal Title: Exp. Hematol. Volume: 39 Pages: 424-433
  • NAID: 120002970837
  • Peer Reviewed
• [Journal Article] Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis : a phase I/II clinical trial, following preclinical studies to ensure safety (2011)
  • Author(s): Ido A, Moriuchi A, Numata M, Murayama T, Teramukai S, Marusawa H, Yamaji N, Setoyama H, Kim ID, Chiba T, Higuchi S, Yokode M, Fukushima M, Shimizu A., Tsubouchi H.
  • Journal Title: J. Transl. Med. Volume: 9 Pages: 55-55
  • Peer Reviewed
• [Journal Article] Runx3 is required for full activation of regulatory T cells to prevent colitis-associated tumor formation. (2011)
  • Author(s): Sugai, M., Aoki, K., Osato, T., Nambu, Y., Ito, K., Taketo, M. M., Ito, Y. and Shimizu, A.
  • Journal Title: J. Immunol, Volume: 186 Issue: 11 Pages: 6515-6520
  • DOI: 10.4049/jimmunol.1001671
  • Peer Reviewed
• [Journal Article] Cross-priming of CD8(+) T cells in vivo by dendritic cells pulsed with autologous apoptotic leukemic cells in immunotherapy for elderly patients with acute myeloid leukemia. (2011)
  • Author(s): Kitawaki, T., Kadowaki, N., Fukunaga, K., Kasai, Y., Maekawa, T., Ohmori, T., Itoh, T., Shimizu, A., Kuzushima, K., Kondo, T., Ishikawa, T.and Uchiyama, T.
  • Journal Title: Exp. Hematol. Volume: 39 Issue: 4 Pages: 424-433
  • DOI: 10.1016/j.exphem.2011.01.001
  • NAID: 120002970837
  • Peer Reviewed
• [Journal Article] Safety and pharmacokinetics of recombinant human hepatocyte growth factor (rh-HGF) in patients with fulminant hepatitis: a phase I/II clinical trial, following preclinical studies to ensure safety. (2011)
  • Author(s): Ido A, Moriuchi A, Numata M, Murayama T, Teramukai S, Marusawa H, Yamaji N, Setoyama H, Kim ID, Chiba T, Higuchi S, Yokode M, Fukushima M, Shimizu A. and Tsubouchi H.
  • Journal Title: J. Transl. Med. Volume: 9 Issue: 1 Pages: 55-55
  • DOI: 10.1186/1479-5876-9-55
  • Peer Reviewed
• [Journal Article] Runx3 is required for full activation of regulatory T cells to prevent colitis-assocfated tumor formation. (2011)
  • Author(s): Sugai, M., et al.
  • Journal Title: J.Immunol. Volume: 186(印刷中)
  • Peer Reviewed
• [Journal Article] Requirement for Runx proteins in IgA class switching acting downstream of TGF-β1 and retinoic acid signaling (2010)
  • Author(s): Watanabe, K., Sugai, M., Nambu, Y., Osato, M., Hayashi, T., Kawaguchi, M., Komori, T., Ito, Y., Shimizu, A.
  • Journal Title: J. Immunol. Volume: 184 Pages: 2785-2792
  • Peer Reviewed
• [Journal Article] Functions of Runx in IgA class switch recombination (2010)
  • Author(s): Sugai, M., Watanabe, K., Nambu, Y., Hayashi, T., Shimizu, A.
  • Journal Title: J. Cell. Biochem. Volume: 112 Pages: 409-414
  • Peer Reviewed
• [Journal Article] Graded attenuation of TCR signaling elicits distinct autoimmune diseases by altering thymic T cell selection and regulatory T cell function (2010)
  • Author(s): Tanaka, S., Maeda, S., Hashimoto, M., Fujimori, C., Ito, Y., Teradaira, S., Hirota, K., Yoshitomi, H., Katakai, T., Shimizu, A., Nomura, T., Sakaguchi,N., Sakaguchi, S.
  • Journal Title: J. Immunol. Volume: 185 Pages: 2295-2305
  • Peer Reviewed
• [Journal Article] Functions of Runx in IgA class switch recombination. (2010)
  • Author(s): Sugai, M., et al.
  • Journal Title: J.Cell.Biochem. Volume: 114 Pages: 409-414
  • Peer Reviewed
• [Journal Article] Graded attenuation of TCR signaling elicits distinct autoimmune diseases by altering thymic T cell selection and regulatory T cell function.. (2010)
  • Author(s): Tanaka, S., et al.
  • Journal Title: J.Immunol. Volume: 185 Pages: 2295-2305
  • Peer Reviewed
• [Journal Article] Requirement for Runx proteins in IgA class switching acting downstream of TGF-β1 and retinoic acid signaling (2010)
  • Author(s): Watanabe, K., et al.
  • Journal Title: J.Immunol 184 Pages: 2785-2792
  • Peer Reviewed
• [Journal Article] CXCL13 production by an established lymph node stromal cell line via lymphotoxin-beta receptor engagement involves the cooperation of multiple signaling pathways (2009)
  • Author(s): Suto, H., Katakai, T., Sugai, M., Kinashi, T., Shimizu, A.
  • Journal Title: Int Immunol. Volume: 21 Pages: 467-476
  • NAID: 10025385782
  • Peer Reviewed
• [Journal Article] UGT1A1*6 polymorphism is most predictive of severe neutropenia induced by irinotecan in Japanese cancer patients (2009)
  • Author(s): Onoue, M., Terada, T., Kobayashi, M., Katsura, T., Matsumoto, S., Yanagihara, K., Nishimura, T., Kanai, M., Teramukai, S., Shimizu, A., Fukushima, M., Inui, K.
  • Journal Title: Intnat. J. Clin. Oncol. Volume: 14 Pages: 136-142
  • NAID: 10025147852
  • Peer Reviewed
• [Journal Article] CXCL13 production by an established lymph node stromal cell line via lymphotoxin-β receptor engagement involves the cooperation of multiple signaling pathways (2009)
  • Author(s): Suto, H., et al.
  • Journal Title: Int.Immunol 21 Pages: 467-476
  • Peer Reviewed
• [Journal Article] UGT1A1*6 polymorphism is most predictive of severe neutropenia induced by irinotecan in Japanese cancer patients (2009)
  • Author(s): Onoue, M., et al.
  • Journal Title: Int.J.Oncol 14 Pages: 136-142
  • Peer Reviewed