Establishment of transgenic mice that recognize bacteria specific antigen and develop spontaneous colitis under specific pathogen free condition.

• Project/Area Number: 15590627
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: KANAI Takanori Tokyo Medical and Dental Univ., Dept.of Gastroenteorology and Hepatology, Assistant professor, 医学部・附属病院, 講師 (40245478)
• Co-Investigator(Kenkyū-buntansha): WATANABE Mamoru Tokyo Medical and Dental Univ., Dept.of Gastroenteorology and Hepatology, Professor, 大学院・医歯学総合研究科, 教授 (10175127) ; YAGITA Hideo Juntendo Univ., Dept.of Immunology, 医学部, 助教授 (30182306) ; HIBI Toshifumi Keio Univ., Dept.of Internal Medicine, 医学部, 教授 (50129623)
• Project Period (FY): 2003 – 2004
• Project Status: Completed (Fiscal Year 2004)
• Budget Amount: ¥3,500,000 (Direct Cost: ¥3,500,000); Fiscal Year 2004: ¥1,500,000 (Direct Cost: ¥1,500,000); Fiscal Year 2003: ¥2,000,000 (Direct Cost: ¥2,000,000)
• Keywords: inflammatory bowel diseases / murine model / Antigen-specific / Crohn's disease / Ulcerative colitis / Probiotics / Cell transfer / Transgenic mice / 調節性T細胞 / 慢性大腸炎 / 調節製T細胞 / 腸管粘膜免疫 / 単クローン / 慢性大腸炎モデル / 自然免疫 / 腸内細菌 / 自己免疫疾患

Research Abstract

In this study, we clarified that intestinal bacteria flora is essential for the development of chronic colitis using murine model of chronic colitis. We in general used adoptive transfer model that normal CD4+CD45RBhigh T cells from spleens are transferred into SCID mice. This model has the strong advadvantages that we can exactly evaluate the pathogenic T cells in clonal level.
We are now under investigation to establish bacteria-specidfic antigen recognizing TCR transgenic mouse after the isolation of TCRab genes. Using this model, we believe that we can brake through to understand the exact mechanism of action in terms of antigen-specific analysis. Furthermore, we will find out a new strategy using probiotics for the treatment of inflammatory bowel diseases.

Research Products

• [Journal Article] MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis. (2005)
  • Author(s): Araki A, Kanai T, et al.
  • Journal Title: J Gastroenterol 40 Pages: 16-23
  • NAID: 10014370953
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] IL-7 exacerbates chronic colitis with expansion of memory IL-7R^<high>CD4^+ mucosal T cells in mice. (2005)
  • Author(s): Okada E, Yamazaki M, Tanabe M, Takeuchi T, Nanno M, Oshima S, Okamoto R, Tsuchiya K, Nakamura T, Kanai T, Hibi T, Watanabe M.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol 288 Pages: 745-754
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] MyD88-deficient mice develop severe intestinal inflammation in dextran sodium sulfate colitis. (2005)
  • Author(s): Araki A, Kanai T, Ishikura T, Makita S, Uraushihara K, Iiyama R, Totsuka T, Takeda K, Akira S, Watanabe M.
  • Journal Title: J Gastroenterol 40 Pages: 16-23
  • NAID: 10014370953
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Clinical significance of microsatellite instability in the inflamed mucosa for the prediction of colonic neoplasms in patients with ulcerative colitis. (2005)
  • Author(s): Tahara T, Inoue N, Hisamatsu T, Kashiwagi K, Takaishi H, Kanai T, Watanabe M, Ishii H, Hibi T.
  • Journal Title: J Gastrornt Hepatol 20 Pages: 710-715
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ectopic CD40 ligand expression on B cells triggers intestinal inflammation. (2004)
  • Author(s): Kawamura T, Kanai T, et al.
  • Journal Title: J Immunol 172 Pages: 6388-6397
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Hyperexpression of inducible costimulator and its contribution on lamina propria T cells in inflammatory bowel disease. (2004)
  • Author(s): Sato T, Kanai T, et al.
  • Journal Title: Gastroenterology 126 Pages: 829-839
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Blockade of B7-H1 suppresses the development of chronic intestinal inflammation. (2004)
  • Author(s): Kanai T, et al.
  • Journal Title: J Immunol 171 Pages: 4156-4163
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Interferon regulatory factor 1 (IRF-1) and IRF-2 distinctively up-regulate gene expression and production of IL-7 in human intestinal epithelial cells. (2004)
  • Author(s): Oshima S, Kanai T, et al.
  • Journal Title: Mol Cell Biol 24 Pages: 6298-6310
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] CD4^+CD25^<bright>FoxP3^+ regulatory T cells in human intestinal lamina propria. (2004)
  • Author(s): Makita S, Kanai T, et al.
  • Journal Title: J Immunol 173 Pages: 3119-3130
  • Description: 「研究成果報告書概要(和文)」より
• [Journal Article] Human intestinal epithelia-derived IL-18 is a potent prolifrerative factor for intraepithelial lymphocytes synergistically with IL-2, IL-7 and IL-15. (2004)
  • Author(s): Okazawa A, Kanai T, Nakamaru T, Sato T, Inoue N, Ogata H, Iwao Y, Ikeda M, Kawamura T, Makita S, Uraushihara K, Okamoto R, Yamazaki M, Kurimoto M, Ishii H, Watanabe M, Hibi T.
  • Journal Title: Clin Exp Immunol 136 Pages: 269-276
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hyperexpression of inducible costimulator and its contribution on lamina propria T cells in inflammatory bowel disease. (2004)
  • Author(s): Sato T, Kanai T, Watanabe M, Sakuraba A, Okamoto S, Nakai T, Okazawa A, Inoue N, Totsuka T, Yamazaki M, Kroczek RA, Fukushima T, Ishii H, Hibi T.
  • Journal Title: Gastroenterology 126 Pages: 829-839
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] T-bet up-regulation and subsequent interleukin 12 stimulation are essential for the induction of Th1 mediated immunopathology in Crohn's disease. (2004)
  • Author(s): Matsuoka K, Inoue N, Sato T, Okamoto S, Hisamatsu T, Kishi Y, Atsushi Sakuraba A, Hitotsumatsu O, Fukushima T, Kanai T, Watanabe M, Ishii H, Hibi T.
  • Journal Title: Gut 53 Pages: 1303-1308
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ectopic CD40 ligand expression on B cells triggers intestinal inflammation. (2004)
  • Author(s): Kawamura T, Kanai T, Dohi T, Uraushihara K, Totsuka T, Iiyama R, Taneda C, Yamazaki M, Nakamura T, Aiba Y, Tsubata T, Watanabe M.
  • Journal Title: J Immunol 172 Pages: 6388-6397
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hepatitis C virus infection in human liver tissue engrafted in mice with an infectious molecular clone. (2004)
  • Author(s): Maeda N, Watanabe M, Okamoto S, Kanai T, Yamada T, Hata J, Hozumi N, Katsume A, Nuriya H, Sandhu J, Ishii H, Kohara M, Hibi T.
  • Journal Title: Liver Int 24 Pages: 259-267
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Interferon regulatory factor 1 (IRF-1) and IRF-2 distinctively upregulate gene expression and production of interleukin-7 in human intestinal epithelial cells. (2004)
  • Author(s): Oshima S, Nakamura T, Kanai T, Handa H, Watanabe M.
  • Journal Title: Mol Cell Biol 24 Pages: 6298-6310
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] CD4^+CD25^<bright>FoxP3^+ regulatory T cells in human intestinal lamina propria. (2004)
  • Author(s): Makita S, Kanai T, Oshima S, Uraushihara K, Totsuka T, Iiyama R, Sawada T, Nakamura T, Koganei K, Fukushima T, Watanabe M.
  • Journal Title: J Immunol 173 Pages: 3119-3130
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] CD4^+CD25^<bright>FoxP3^+ regulatory T cells in human intestinal lamina propria. (2004)
  • Author(s): Makita S, Kanai T, et al.
  • Journal Title: J Immunology 173 Pages: 3119-3130
• [Journal Article] IRF-1 and IRF-2 distinctively up-regulate gene expression and production of IL-7 in human intestinal epithelial cells. (2004)
  • Author(s): OshimaS, Kanai T, et al.
  • Journal Title: Mol Cell Biol 24 Pages: 6298-6310
• [Journal Article] Hyperexpression of inducible costimulator and its contribution on amina propria T cells in inflammatory bowel disease. (2004)
  • Author(s): Sato T, Kanai T, et al.
  • Journal Title: Gastroenterology 126 Pages: 829-839
• [Journal Article] T-bet up-regulation and subsequent interleukin 12 stimulation are essential for the induction of Thl mediated immunopathology in Crohn's disease. (2004)
  • Author(s): Matsuoka K, Kanai T, et al.
  • Journal Title: Gut 53 Pages: 1303-1308
• [Journal Article] Human intestinal epithelia-derived IL-18 is a potent prolifrerative factor or intraepithelial lymphocytes synergistically with IL-2,IL-7 and IL-15. (2004)
  • Author(s): Okazawa A, Kanai T, et al.
  • Journal Title: Clin Exp Immunol 1362 Pages: 269-276
• [Journal Article] Ameliorating effect of anti-ICOS monoclonal antibody in a murine model of chronic colitis. (2003)
  • Author(s): Totsuka T, Kanai T^#, Iiyama R, Uraushihara K, Yamazaki M, Okamoto R, Hibi T, Tezuka K, Azuma M, Akiba H, Yagita H, Okumura K, Watanabe M.
  • Journal Title: Gastroenterology 124 Pages: 410-421
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Preventive and therapeutic effects of chronic colitis in CD4^+CD45RB^+ T cell-transferred SCID mice by anti-OX40L mAb administration. (2003)
  • Author(s): Totsuka T, Kanai T^#, Uraushihara K, Iiyama R, Akiba H, Yagita H, Okumura K, Watanabe M.
  • Journal Title: Am J Physiol GI & Liver 284
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] A specific genetic alteration on chromosome 6 in ulcerative colitis-associated colorectal cancers. (2003)
  • Author(s): Ezaki, Watanabe M, Inoue N, Kanai T^#, Ogata H, Iwao Y, Ishii H, Hibi T.
  • Journal Title: Cancer Res 63 Pages: 3747-3749
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The role of inducible co-stimulator (ICOS)/B7 related protein-1 (B7RP-1) interaction in the functional development of Peyer's patches. (2003)
  • Author(s): Iiyama R, Kanai T^#, Uraushihara K, Totsuka T, Nakamura T, Miyata T, Yagita H, Kushi A, Suzuki K, Tezuka K, Watanabe M.
  • Journal Title: Immunol Letters 88 Pages: 63-70
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regulation of murine inflammatory bowel disease by CD25^+ and CD25^-CD4^+ Glucocorticoid-induced TNF receptor family-related gene^+ regulatory T cells. (2003)
  • Author(s): Uraushihara K^*, Kanai T^<*, #>, Ko K, Totsuka T, Makita S, Iiyama R, Nakamura T, Watanabe M.
  • Journal Title: J Immunol 171 Pages: 708-716
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] IL-18 overexpression exacerbates the development of colitis with marked infiltrates macrophages in IL-18 transgenic mice. (2003)
  • Author(s): Ishikura T, Kanai T^#, Uraushihara K, Iiyama R, Makita S, Totsuka T, Yamazaki M, Sawada T, Nakamura T, Kitahora T, Hibi T, Hoshino T, Watanabe M.
  • Journal Title: J Gastroenterol Hepatol 18 Pages: 960-969
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Contrasting action of IL-12 and IL-18 in the development of dextran sodium sulfate (DSS) colitis in mice. (2003)
  • Author(s): Takagi H, Kanai T, Okazawa A, Kishi Y, Sato T, Takaishi H, Inoue N, Ogata H, Iwao Y, Hoshino K, Takeda K, Akira S, Ishii H, Watanabe M, Hibi T.
  • Journal Title: Scan J Gastroenterol 33 Pages: 837-844
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Preventive effects of chronic colitis in CD4^+CD45RB^+ T cell-transferred SCID mice by anti-FasL mAb administration. (2003)
  • Author(s): Dan N, Kanai T, Totsuka T, Iiyama R, Yamazaki M, Sawada T, Miyata T, Yagita H, Okumura K, Watanabe M.
  • Journal Title: Am J Physiol GI & Liver 285
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] The role of cryptopatch-derived intraepithelial lymphocytes in the development of chronic ileocaetitis. (2003)
  • Author(s): Makita S, Kanai T, Matsumoto S, Iiyama R, Uraushihara K, Totsuka T, Yamazaki M, Nakamura T, Ishikawa H, Watanabe M.
  • Journal Title: Scan J Immunol 58 Pages: 428-435
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Hyperexpression of inducible costimulator (ICOS) on lamina propria mononuclear cells in rat dextran sulfate sodium (DSS). (2003)
  • Author(s): Ishii K, Kanai T, Ishikura T, Totsuka T, Uraushihara K, Yamazaki M, Okamoto R, Araki A, Ohka S, Miyata T, Nakamura T, Kitahora T, Hibi T, Tezuka K, Watanabe M.
  • Journal Title: J Gastroenterol Hepatol 19 Pages: 174-181
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Mucosal T cells expressing high levels of IL-7 receptor are potential targets for treatment of chronic colitis. (2003)
  • Author(s): Yamazaki M, Yajima T, Tanabe M, Fukui K, Okada E, Okamoto R, Oshima S, Nakamura T, Kanai T, Takeuchi T, Uehira M, Ishikawa H, Hibi T, Watanabe M.
  • Journal Title: J Immunol 171 Pages: 1556-1563
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Blockade of B7-H1 suppresses the development of chronic intestinal inflammation. (2003)
  • Author(s): Kanai T, Totsuka T, Uraushihara K, Makita S, Nakamura T, Koganei K, Fukushima T, Akiba H, Yagita H, Okumura K, Machida U, Iwai H, Azuma M, Chen L, Watanabe M.
  • Journal Title: J Immunol 171 Pages: 4156-4163
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Morphological and functional abnormalities of Peyer's patch in MyD88-deficient mice. (2003)
  • Author(s): Iiyama R, Kanai T, Uraushihara K, Ishikura T, Makita S, Totsuka T, Yamazaki M, Nakamura T, Miyata T, Yoshida H, Takeuchi O, Hoshino K, Takeda K, Ishikawa H, Akira S, Watanabe M.
  • Journal Title: Scan J Immunol 58 Pages: 620-627
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Increase of bone marrow-derived secretory lineage epithelial cells during regeneration in the human intestine.
  • Author(s): Matsumoto T, Okamoto R, Yagima T, Mori T, Okamoto S, Ikeda Y, Yamazaki M, Oshima S, Tsuchiya K, Nakamura T, Kanai T, Okano H, Inazawa J, Hibi T, Watanabe M.
  • Journal Title: Gastroenterology (in the press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Ameliorating effect of saporin-conjugated anti-CD11b monoclonal antibody in a murine T-cell-mediated chronic colitis.
  • Author(s): Kanai T^#, Uraushihara K, Totsuka T, Nemoto Y, Fujii R, kawamura T, Makita S, Yagita H, Okumura K, Watanabe M.
  • Journal Title: J Gastrornt Hepatol (in the press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Regulation of murine chronic colitis by CD4^+CD25^-Programed Death-1^+ T cells.
  • Author(s): Totsuka T, Kanai T, Makita S, Fujii R, Nemoto Y, Oshima S, Okamoto R, Koyanagi A, Akiba H, Okumura K, Yagita H, Watanabe M.
  • Journal Title: Eur J Immunol (in the press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] IRF-inducing proteosomes in human intestinal epithelial cells.
  • Author(s): Namiki S, Nakamura T, Oshima S, Tsuchiya K, Kanai T, Watanabe M.
  • Journal Title: FEBES J (in the press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Book] 外科 (2004)
  • Author(s): 岡田英理子, 金井隆典, 渡辺守
  • Description: 「研究成果報告書概要(和文)」より
• [Publications] Totsuka T, Kanai T, et al.: "Ameliorating effect of anti-inducible co-stimulator monoclonal antibody in a murine model of chronic colitis."Gastroenterology. 124. 410-421 (2003)
• [Publications] Ezaki T, Kanai T, et at.: "A specific genetic alteration on chromosome 6 in ulcerative colitis-associated colorectal cancers."Cancer Res. 63. 3747-3749 (2003)
• [Publications] Uraushihara K, Kanai T, et al.: "Regulation of murine inflammalory bowel disease by CD25+ and CD25-CD4+ glucocorticoid-induced TNF receptor family-related gene+ regulatory T cells."J Immunol. 171. 708-716 (2003)
• [Publications] Yanazaki M, Kanai T, et al.: "Mucosal T cells exoressing high levels of IL-7 receptor are potential targets for treatment of chronic colitis."J Immunol. 171. 1556-1563 (2003)
• [Publications] Kanai T, et al.: "Blockade of B7-H1 suppresses the development of chronic intestinal inflammation."J Immunol. 171. 4156-4163 (2003)
• [Publications] Dan N, Kanai T, et al.: "Preventive effects of chronic colitis in CD4^+CD45RB^+T cell-transferred SCID mice by anti-FasL mAb administration."Am J Physiol GI & Liver. 285. 754-760 (2003)