骨髄腸管間を循環する腸炎惹起免疫記憶T細胞の全身播種性を制御する新規治療法の開発

2008 Fiscal Year Annual Research Report

• Project/Area Number: 19390197
• Research Institution: Keio University
• Principal Investigator: 金井 隆典 Keio University, 医学部, 准教授 (40245478)
• Co-Investigator(Kenkyū-buntansha): 渡辺 守 東京医科歯科大学, 大学院・医歯学総合研究科, 教授 (10175127) ; 永石 宇司 東京医科歯科大学, 大学院・医歯学総合研究科, 寄付講座教員 (60447464) ; 戸塚 輝治 東京医科歯科大学, 医学部附属病院, 助教 (70447465)
• 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

Research Abstract

慢性大腸炎モデル末梢血に腸炎責任CD4+T細胞が存在するか?
IBDモデル、CD4+CD45RBhigh T細胞移入SCID大腸炎マウスにおいて、腸炎責任CD4+T細胞は発症初期ばかりではなく腸炎完成後においても恒常的に全身に循環していることを明らかとした(Inflam Bowel Dis.2009)。また、FTY720による腸炎責任CD4+T細胞の循環遮断は腸炎発症を抑制することを明らかとした(Eur J Immunol. 2008)。以上、IBDを腸管局所の消化管疾患ではなく全身疾患として捉える必要性を示唆するものと言える。
末梢血腸炎責任CD4+T細胞は骨髄に移入するか?
腸炎骨髄CD4+T細胞の維持メカニズムの検討
これら、全身性腸炎責任CD4+T細胞はIL-7を産生する骨髄にも存在し、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パラビオーシス実験によって証明した(Inflam Bowel Dis. 2008、J Immunol 2008)。さらに、腸炎責任CD4+T細胞は様々なTLR分子を発現し、TLRを介した刺激は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(J Immunol(2) 2008)。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(J Immunol投稿中)

Research Products

• [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 Pages: G23-35
  • 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 Pages: G850-859
  • 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] 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 Pages: G199-207
  • 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
• [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, 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