Circulating colitogenic CD4+ memory T cells between bone marrow and intestine may be targets for the treatment of inflammatory bowel diseases

• Project/Area Number: 19390197
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Keio University (2008); Tokyo Medical and Dental University (2007)
• Principal Investigator: KANAI Takanori Keio University, 医学部, 准教授 (40245478)
• Co-Investigator(Kenkyū-buntansha): WATANABE Manabu 東京医科歯科大学, 医歯(薬)学総合研究科, 教授 (10175127) ; TOTSUKA Teruji 東京医科歯科大学, 医学部・附属病院, 助教 (70447465) ; NAGAISHI Takashi 東京医科歯科大学, 医歯(薬)学総合研究科, メディカルフェロー (60447464)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥17,810,000 (Direct Cost: ¥13,700,000、Indirect Cost: ¥4,110,000); Fiscal Year 2008: ¥7,020,000 (Direct Cost: ¥5,400,000、Indirect Cost: ¥1,620,000); Fiscal Year 2007: ¥10,790,000 (Direct Cost: ¥8,300,000、Indirect Cost: ¥2,490,000)
• Keywords: 炎症性腸疾患 / 腸炎責任CD4 T 細胞 / 免疫記憶T 細胞 / IL-7 / 慢性大腸炎モデル / 腸炎責任CD4 T細胞 / 免疫記憶T細胞 / 大腸炎 / マウスモデル / 骨髄 / 免疫記憶細胞

Research Abstract

マウス大腸炎モデルにおいて腸炎責任CD4T細胞は腸炎完成後恒常的に全身循環し、循環遮断は腸炎発症を抑制することを明らかとした。腸炎責任CD4T細胞はIL-7産生骨髄にも存在し、腸管IL-7欠損状態においても骨髄IL-7によって維持されることを並体結合実験で証明した。さらに、腸炎責任CD4T細胞はTLR分子を発現し、MyD88分子を介し病態恒常性に寄与することを明らかとした。また、無菌マウスにおいても腸炎発症を認めることはないものの腸炎責任CD4 T細胞は恒常的生体内で長期維持されることを証明した。

Research Products

• [Journal Article] Homeostatic (IL-7) and effector (IL-17) cytokines as distinct but complementary target for an optimal therapeutic strategy in inflammatory bowel disease (2009)
  • Author(s): Kanai T, Nemoto Y, Kamada N, Totsuka T, Hisamatsu T, Watanabe M, Hibi T.
  • Journal Title: Curr Opin GastroenterolEpub ahead of print(Curr Opin Gastroenterol)
  • Peer Reviewed
• [Journal Article] RANK-RANKL signaling pathway is critically involved in the function of CD4+CD25+ regulatory T cells in chronic colitis (2009)
  • Author(s): Totsuka T, Kanai T, Nemoto Y, Tomita T, Okamoto R, Tsuchiya K, Nakamura T, Sakamoto N, Akiba H, Okumura K, Yagita H, Watanabe M.
  • Journal Title: J Immunol 182 Pages: 6079-6087
  • Peer Reviewed
• [Journal Article] Single-operator double-balloon endoscopy (DBE) is as effective as dual-operator DBE (2009)
  • Author(s): Araki A, Tsuchiya K, Okada E, Suzuki S, Oshima S, Yoshioka S, Yoshioka A, Kanai T, Watanabe M.
  • Journal Title: J Gastroenterol Hepatol(Epub ahead of print)
  • Peer Reviewed
• [Journal Article] Musashi-1 suppresses expression of Paneth cell-specific genes in human intestinal epithelial cells (2009)
  • Author(s): Murayama M, Okamoto R, Tsuchiya K, Akiyama J, Nakamura T, Sakamoto N, Kanai T, Watanabe M.
  • Journal Title: J Gastroenterol 44 Pages: 173-182
  • NAID: 10025173646
  • Peer Reviewed
• [Journal Article] Signaling pathway via TNF-alpha/NF-kappaB in intestinal epithelial cells may be directly involved in colitis-associated carcinogenesis (2009)
  • Author(s): Onizawa M, Nagaishi T, Kanai T, Nagano K, Oshima S, Nemoto Y, Yoshioka A, Totsuka T, Okamoto R, Nakamura T, Sakamoto N, Tsuchiya K, Aoki K, Ohya K, Yagita H, Watanabe M.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol 296 Pages: 850-859
  • Peer Reviewed
• [Journal Article] Requirement of Notch activation during regeneration of the intestinal epithelia (2009)
  • Author(s): Okamoto R, Tsuchiya K, Nemoto Y, Akiyama J, Nakamura T, Kanai T, Watanabe M.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol 296 Pages: 23-35
  • Peer Reviewed
• [Journal Article] Persistent retention of colitogenic CD4+ memory T cells causes inflammatory bowel diseases to become intractable (2009)
  • Author(s): Kanai T, Nemoto Y, Tomita T, Totsuka T, Watanabe M, Hibi T.
  • Journal Title: Inflamm Bowel Dis. 15 Pages: 926-934
  • Peer Reviewed
• [Journal Article] Requirement of Notch activation during regeneration of the intestinal epithelia. (2009)
  • Author(s): Okamoto R, Tsuchiya K, Nemoto Y, Akiyama J, Nakainura T, Kanai T, Watanabe M.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. 296
  • Peer Reviewed
• [Journal Article] Signaling pathway via TNF-{alpha}/NF-{kappa} B in intestinal epithelial cells may be directly involved in Colitis-associated carcinogenesis. (2009)
  • Author(s): Oni zawa M, Nagaishi T, Kanai T, Nagano K, 0shima S, Kemoto Y, Yoshi oka A, Totsuka T, Okamoto R, Nakamura T, Sakamoto N, Tsuchiya K, Aoki K, Ohya K, Yagita H, Watanabe M
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. 296
  • Peer Reviewed
• [Journal Article] RANKL (2009)
  • Author(s): Totsuka T, Kanai T, Watanabe M.
  • Journal Title: J Immunol in press
  • Peer Reviewed
• [Journal Article] Signaling pathway via TNF-{alpha}/NF-{kappa} B in intestinalepithelial cells may be directly involved in colitis-associatedcarcinogenesis. (2009)
  • Author(s): Kanai T, Nemoto Y, Kamata M, Hisamatsu T, Watanabe M, Hibi T
  • Journal Title: Curr Opin Gastroenterol in press
  • Peer Reviewed
• [Journal Article] Persistent retention of Colitogenic CD4(+)memory T cells causes inflammatory bowel diseases to become intractable. (2009)
  • Author(s): kanai T, Nemoto Y, Tomita T, Totsuka T, Watanabe M, Hibi T.
  • Journal Title: Inflamm Bowel Dis in press
  • Peer Reviewed
• [Journal Article] Musashi-l suppresses expression of Paneth cell-specific genes inhuman intestinal epithelial cells. (2009)
  • Author(s): Murayama M, Okamoto R, Tsuchi ya K, Akiyama J, Nakamura T, Sakamoto N, Kanai T, Watanabe M.
  • Journal Title: J Gastroenterol. 44 Pages: 173-182
  • Peer Reviewed
• [Journal Article] Single-operator double-balloon endoscopy (DBE)is as effectiveas dual-operator DBE. (2009)
  • Author(s): Araki A, Tsuchiya K, Okada E, Suzuki S, Oshima S, Yoshioka S, Yoshioka A, Kanai T, Watanabe M.
  • Journal Title: J Gastroenterol Hepatol. in press
  • Peer Reviewed
• [Journal Article] FTY720 suppresses the development of colitis in lymphoid-null mice by modulating the trafficking of colitogenic CD4+ T cells in bone marrow (2008)
  • Author(s): Fujii T, Tomita T, Kanai T, Nemoto Y, Totsuka T, Sakamoto N, Nakamura T, Tsuchiya K, Okamoto R, Watanabe M.
  • Journal Title: Eur J Immunol 38 Pages: 3290-3303
  • Peer Reviewed
• [Journal Article] Single-operator method for double-balloon endoscopy : a pilot study (2008)
  • Author(s): Araki A, Tsuchiya K, Okada E, Suzuki S, Oshima S, Okamoto R, Kanai T, Watanabe M.
  • Journal Title: Endoscopy 40 Pages: 936-938
  • Peer Reviewed
• [Journal Article] Colitogenic CD4+ effector-memory T cells actively recirculate in chronic colitic mice (2008)
  • Author(s): Tomita T, Kanai T, Nemoto Y, Fujii T, Nozaki K, Okamoto R, Tsuchiya K, Nakamura T, Sakamoto N, Totsuka T, Watanabe M.
  • Journal Title: Inflamm Bowel Dis. 14 Pages: 1630-1640
  • Peer Reviewed
• [Journal Article] Flagellin stimulation suppresses IL-7 secretion of intestinal epithelial cells (2008)
  • Author(s): Yoshioka A, Okamoto R, Oshima S, Akiyama J, Tsuchiya K, Nakamura T, Kanai T, Watanabe M.
  • Journal Title: Cytokine 44 Pages: 57-64
  • Peer Reviewed
• [Journal Article] Negative feedback regulation of colitogenic CD4+ T cells by increased granulopoiesis (2008)
  • Author(s): Nemoto Y, Kanai T, Tohda S, Totsuka T, Okamoto R, Tsuchiya K, Nakamura T, Sakamoto N, Fukuda T, Miura O, Yagita H, Watanabe M
  • Journal Title: Inflamm Bowel Dis. 14 Pages: 1491-1503
  • Peer Reviewed
• [Journal Article] Inducible expression of microRNA-194 is regulated by HNF-1alpha during intestinal epithelial cell differentiation (2008)
  • Author(s): Hino K, Tsuchiya K, Fukao T, Kiga K, Okamoto R, Kanai T, Watanabe M.
  • Journal Title: RNA 14 Pages: 1433-1442
  • Peer Reviewed
• [Journal Article] Immunosenescent colitogenic CD4(+) T cells convert to regulatory cells and suppress colitis (2008)
  • Author(s): Totsuka T, Kanai T, Nemoto Y, Tomita T, Tsuchiya K, Sakamoto N, Okamoto R, Watanabe M.
  • Journal Title: Eur J Immunol 38 Pages: 1275-1286
  • Peer Reviewed
• [Journal Article] Continuous generation of colitogenic CD4(+) T cells in persistent colitis (2008)
  • Author(s): Tomita T, Kanai T, Fujii T, Nemoto Y, Okamoto R, Tsuchiya K, Totsuka T, Sakamoto N, Watanabe M.
  • Journal Title: Eur J Immunol 38 Pages: 1264-1274
  • Peer Reviewed
• [Journal Article] MyD88-dependent pathway in T cells directly modulates the expansion of colitogenic CD4+ T cells in chronic colitis (2008)
  • Author(s): Tomita T, Kanai T, Fujii T, Nemoto Y, Okamoto R, Tsuchiya K, Totsuka T, Sakamoto N, Akira S, Watanabe M.
  • Journal Title: J Immunol 180 Pages: 5291-5299
  • Peer Reviewed
• [Journal Article] Proteasomal degradation of Atoh1 by aberrant Wnt signaling maintains the undifferentiated state of colon cancer (2008)
  • Author(s): Aragaki M, Tsuchiya K, Okamoto R, Yoshioka S, Nakamura T, Sakamoto N, Kanai T, Watanabe M.
  • Journal Title: Biochem Biophys Res Commun 368 Pages: 923-929
  • Peer Reviewed
• [Journal Article] Current pharmacologic therapies and emerging alternatives in the treatment of ulcerative colitis (2008)
  • Author(s): Nakamura T, Nagahori M, Kanai T, Watanabe M.
  • Journal Title: Digestion 77 Pages: 36-41
  • Peer Reviewed
• [Journal Article] Systemic, but not intestinal, IL-7 is essential for the persistence of chronic colitis (2008)
  • Author(s): Tomita T, Kanai T, Nemoto Y, Totsuka T, Okamoto R, Tsuchiya K, Sakamoto N, Watanabe M.
  • Journal Title: J Immunol 180 Pages: 383-390
  • Peer Reviewed
• [Journal Article] Development of plaque assays for hepatitis C virus-JFH1 strain and isolation of mutants with enhanced cytopathogenicity and replication capacity (2008)
  • Author(s): Sekine-Osajima Y, Sakamoto N, Mishima K, Nakagawa M, Itsui Y, Tasaka M, Nishimura-Sakurai Y, Chen CH, Kanai T, Tsuchiya K, Wakita T, Enomoto N, Watanabe M.
  • Journal Title: Virology 371 Pages: 71-85
  • Peer Reviewed
• [Journal Article] Blockade of NKG2D signaling prevents the development of murine CD4+ T cell-mediated colitis (2008)
  • Author(s): Ito Y, Kanai T, Totsuka T, Okamoto R, Tsuchiya K, Nemoto Y, Yoshioka A, Tomita T, Nagaishi T, Sakamoto N, Sakanishi T, Okumura K, Yagita H, Watanabe M.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol 294 Pages: 199-207
  • Peer Reviewed
• [Journal Article] MyD88-dependent pathway in T cells directly modulates the expansion of colitogenic CD4^+ T cells in chronic colitis. (2008)
  • Author(s): Tomita T, Kanai T, Fujii T, Nemoto Y, Okamoto R, Tsuchiya K, Totsuka T, Sakamoto N, Akira S, Watanabe M.
  • Journal Title: J Immunol. 180 Pages: 5291-5299
  • Peer Reviewed
• [Journal Article] Immunosenescent colitogenic CD4^+ T cells convert to regulatory cells and suppress colitis. (2008)
  • Author(s): Totsuka T, Kanai T, Nemoto Y, Tomita T, Tsuchiya K, Sakamoto N, Okamoto R, Watanabe M.
  • Journal Title: Eur J Immunol. 38 Pages: 1275-1286
  • Peer Reviewed
• [Journal Article] Continuous generation of colitogenic CD4^+ T cells in persistent colitis. (2008)
  • Author(s): Toraita T, Kanai T, Fujii T, Nemoto Y, Okaraoto R, Tsuchiya K, Totsuka T, Sakamoto N, Watanabe M.
  • Journal Title: Eur J Immunol. 38 Pages: 1264-1274
  • Peer Reviewed
• [Journal Article] Inducible expression of micro RNA-194 is regulated by INF 1 during intestinal epithelial cell differntiation. (2008)
  • Author(s): Hino K, Tsuchiya K, Fukao T, Kiga K. Okamoto R, Kanai T, Watanabe M.
  • Journal Title: RNA. 14 Pages: 1433-1442
  • Peer Reviewed
• [Journal Article] Flagellin stimulation suppresses IL-7 secretion of intestinal epithelial cells. (2008)
  • Author(s): Yoshioka A, Okamoto R, Oshima S, Akiyama J, Tsuchiya K, Nakamura T, Kanai T, Watanabe M.
  • Journal Title: Cytokine 44 Pages: 57-64
  • Peer Reviewed
• [Journal Article] Colitogenic CD4^+ effector-memory T cells actively recirculate in chronic colitic mice. (2008)
  • Author(s): Tomita T, Kanai T, Nemoto Y, Fujii T, Nozaki K, Okamoto R, Tsuchiya K, Nakamura T, Sakamoto N, Totsuka T, Watanabe M.
  • Journal Title: Inflamm Bowel Dis. 14 Pages: 1630-1640
  • Peer Reviewed
• [Journal Article] Single-operator method for double-balloon endoscopy : a pilot study. (2008)
  • Author(s): Araki A, Tsuchiya K, Okada E, Suzuki S, Oshima S, Okamoto R, Kanai T, Watanabe M.
  • Journal Title: Endoscopy. 40 Pages: 963-938
  • Peer Reviewed
• [Journal Article] FTY720 suppresses the development of colitis in lyinphoid-null mice by modulating the trafficking of colitogenic CD4+ T cells in bone marrow. (2008)
  • Author(s): Fujii T, Tomita T, Kanai T, Nemoto Y, Totsuka T, Sakamoto N, Nakamura T, Tsuchiya K, Okamoto R, Watanabe M.
  • Journal Title: Eur J Immunol. 38 Pages: 3290-3303
  • Peer Reviewed
• [Journal Article] Current pharmacologic therapies and emerging alternatives in the treatment of ulcerative colitis. (2008)
  • Author(s): Nakamura T, Nagahori M, Kanai T, Watanabe M.
  • Journal Title: Digestion. 77 Pages: 36-41
  • Peer Reviewed
• [Journal Article] Systemic, but not intestinal, IL-7 is essential for the persistence of chronic colitis. (2008)
  • Author(s): Tomita T, Kanai T, Nemoto Y, Totsuka T, Okamoto R, Tsuchiya K, Sakamoto N, Watanabe M.
  • Journal Title: J Immunol 180 Pages: 383-390
  • Peer Reviewed
• [Journal Article] Proteasomal degradalion of Atohl by aberrant Wnt signaling maintains the undifferentiated state of colon cancer. (2008)
  • Author(s): Aragnki M, Tsuchiya K, Okamoto R, Yoshioka S. Nakamura T, Sakamoto N, Kanai T, Watanabe M.
  • Journal Title: Biochem Biophys Res Commun 368 Pages: 923-929
  • Peer Reviewed
• [Journal Article] Blockade of NKG2D signaling prevents the development of marine CD4^+ T cell-mediated colitis. (2008)
  • Author(s): Ito Y, Kanai T, Totsuka T, Okamoto R, Tsuchiya K, Nemoto Y, Yoshioka A, Tomita T, Nagaishi T, Sakamoto N, Sakanishi T, Okumura K, Yagita H, Watanabe M
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. 294
  • Peer Reviewed
• [Journal Article] Development of plaque assays for hepatitis C virus-JFH1 strain and isolation of mutants with enhanced cytopath ogenicity and replication capacity. (2008)
  • Author(s): Sekine-Osajima Y, Sakamoto N, Mishima K, Nakagawa M, Itsui Y, Tasaka M, Nishimura-Sakurai Y, Chen CH, Kanai T, Tsuchiya K, Wakita T, Enomoto N, Watanabe M.
  • Journal Title: Virology. 37 Pages: 71-85
  • Peer Reviewed
• [Journal Article] Systemic, but not intestinal, IL-7 is essential for the persistence of chronic colitis. (2008)
  • Author(s): Tomita T, Kanai T, et. al.
  • Journal Title: Journal of Immunology 180 Pages: 383-390
  • Peer Reviewed
• [Journal Article] Immunosenescent colitogenic CD4+ T cells convert to regulatory cells and suppress colitis. (2008)
  • Author(s): Totsuka T, Kanai T, et. al.
  • Journal Title: European Journal of Immunology (in press)
  • Peer Reviewed
• [Journal Article] Blockade of NKG2D signaling prevents the development of murine CD4^+ T cell-mediated colitis. (2008)
  • Author(s): Ito Y, Kanai T, et. al.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol 294 Pages: 199-307
  • Peer Reviewed
• [Journal Article] MyD88-dependent pathway in T cells directly modulates the expansion of colitogenic CD4^+ T cells in chronic colitis. (2008)
  • Author(s): Tomita T, Kanai T, et. al.
  • Journal Title: Journal of Immunology (In press)
  • Peer Reviewed
• [Journal Article] Bone marrow retaining colitogenic CD4+ T cells may be a pathogenic reservoir for chronic colitis. (2007)
  • Author(s): Nemoto Y, Kanai T, et. al.
  • Journal Title: Gastroenterology 132 Pages: 176-189
  • NAID: 40015644486
  • Peer Reviewed
• [Journal Article] Extracorporeal elimination of TNF-alpha-producing CD14dullCD16+monocytes in leukocytapheresis therapy for ulcerative colitis. (2007)
  • Author(s): Kanai T, Makita S, et. al.
  • Journal Title: Inflam Bowel Dis 13 Pages: 284-290
  • Peer Reviewed
• [Journal Article] IL-7 is essential for the development and the persistence of chronic colitis. (2007)
  • Author(s): Totsuka T, Kanai T, et. al.
  • Journal Title: Journal of Immunology 178 Pages: 4737-4748
  • Peer Reviewed
• [Presentation] IL-17を標的とした腸炎惹起性メモリーT細胞の制御 (2008)
  • Author(s): 根本康宏、金井隆典、渡辺守
  • Organizer: 第50回日本消化器病学会
  • Place of Presentation: 東京
  • Year and Date: 2008-10-03
• [Presentation] Negatibe feedback regulation of pathogenic CD4+T Cells by increased granulopoiesis (2008)
  • Author(s): Nemoto T, Kanai T, Tohda S, Tptsuka T, Okamoto R, TsuchiyaK, Fukuda T, Yagita H, and Watanabe M.
  • Organizer: 109^<th> Annual meeting of the AGA Institute
  • Place of Presentation: San Doego, CA
  • Year and Date: 2008-05-20
• [Presentation] Negatibe feedback regulation of pathogenic CD4+T Cells by increased granulopoiesis. (2008)
  • Author(s): Nemoto T, Y, Kanai T, Tohda S, Tptsuka T Okamoto R, Tsuchiya K, Fukuda T, Yagita H, Watanabe M.
  • Organizer: 109^<th> Annual meeting of the AGA Institute
  • Place of Presentation: San Doego, CA
  • Year and Date: 2008-05-20
• [Presentation] Uniqueness of colitogenic lamina propria CD4+ T cells for the perpetuation of colitis. (2007)
  • Author(s): Kanai T, Nemoto Y, et. al.
  • Organizer: ICMI2007
  • Place of Presentation: 東京
  • Year and Date: 2007-07-11