自己類似腸内細菌に対する末梢性免疫寛容の生体ライフスパンとその破綻

• Project/Area Number: 20060010
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Keio University
• Principal Investigator: 金井 隆典 Keio University, 医学部, 准教授 (40245478)
• Project Period (FY): 2008 – 2009
• Project Status: Completed (Fiscal Year 2009)
• Budget Amount: ¥9,600,000 (Direct Cost: ¥9,600,000); Fiscal Year 2009: ¥4,800,000 (Direct Cost: ¥4,800,000); Fiscal Year 2008: ¥4,800,000 (Direct Cost: ¥4,800,000)
• Keywords: 炎症性腸疾患 / 免疫記憶細胞 / Interleukin-7 / 難治性 / 永続性 / 慢性大腸炎モデル / 免疫学的記憶 / 腸内細菌 / 免疫学的加齢 / 免疫抑制 / IL-7 / 無菌マウス / Germ free

Research Abstract

我々は免疫難病IBDが永続的に難治化する要因としてIBD免疫病態のプロトタイプを記憶した腸炎惹起性CD4^+メモリーT細胞の永続的潜在性が原因であることを本年度研究計画最終年に解明してきた。
(1)腸炎惹起性CD4^+メモリーT細胞は腸内細菌抗原を認識し、Th1/Th17反応を惹起すると同時に、メモリー化し、生体内に潜在する(Nemoto Y, Kanai T,et al. J Immunol.2009)。
(2)腸炎惹起性CD4^+メモリーT細胞の潜在には、驚くべきことに、腸内細菌の存在は必須ではなく、恒常性サイトカインであるIL-7によって、IL-7が存在する全身臓器により維持されており、IBD治療の根本に抗生剤投与の無効性を指示する証明を行なった(Nemoto Y, Kanai T, et al. J Immunol.2009)。
(3)腸炎惹起性CD4^+メモリーT細胞生存には腸管自身が産生するIL-7ではなく、腸管外で産生されるIL-7が必須であることをパラビオーシス(並体結合)実験を用いて証明した(Tomita T, Kanai T, et al. J Immunol.2009)。
(4)腸炎惹起性CD4^+メモリーT細胞は腸内細菌抗原をT細胞受容体からの刺激以外にT細胞自身が発現するTLR分子を介在し直接、PAMP刺激によって腸炎発症に関与することを証明した(Tomita T, Kanai T, et al. J Immunol.2009)。
(5)腸炎惹起性CD4^+メモリーT細胞は恒常的腸内細菌抗原刺激により免疫学的加齡現象が生じ、抑制性T細胞ヘコンバートする現象を発見した(Totsuka T, Kanai T, et al. Eur J Immunol,2009)。

Research Products

• [Journal Article] Homeostatic (IL-7) and effector (IL-17) cytokines as distinct but complementary target for an optimal therapeutic strategy in inflammatory boweldisease. (2009)
  • Author(s): Kanai T^*, Nemoto Y, Kamada N, Totsuka T, Hisamatsu T, Watanabe M. Hibi T.
  • Journal Title: Curr Opin Gastroenterol. 22 Pages: 306-313
  • Peer Reviewed
• [Journal Article] Human CD14+ macrophages in intestinal lamina propria exhibit potent antigen-presenting ability. (2009)
  • Author(s): Kamada N, Hisamatsu T, Honda H, Kobayashi T, Chinen H, Kitazume MT, Takayama T, Okamoto S, Koganei K, Sugita A, Kanai T, Hibi T.
  • Journal Title: J Immunol. 183 Pages: 1724-1731
  • Peer Reviewed
• [Journal Article] Long-lived colitogenic CD^<4+> memory T cells residing outside the intestine participate in the perpetuation of chronic colitis. (2009)
  • Author(s): Nemoto Y, Kanai T^*, Kameyama K, Shinohara T, Sakamoto N, Totsuka T, Okamoto R, Tsuchiya K, Nakamura T, Sudo T, Matsumoto S, Watanabe M.
  • Journal Title: J Immunol. 183 Pages: 5059-5068
  • 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] IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4+ memory T cells in chronic colitis. (2009)
  • Author(s): Tomita T, Kanai T^*, Totsuka T, Nemoto Y, Okamoto R, Tsuchiya K, Sakamoto N, Ohteki T, Hibi T, Watanabe M.
  • Journal Title: Eur J Immunol. 39 Pages: 2737-2747
  • 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 Bowet Dis. 15 Pages: 926-934
  • Peer Reviewed
• [Journal Article] Signaling pathway via TNFα/NFκB in iatestinal epithelial cells may be directly invotved in colitis-associated carcinogenesis. (2009)
  • Author(s): Onizawa M, Nagaishi T, Kanai T^*, Oshima S, Nemoto Y, Yoshioka A, Totsuka T, Okamoto R, Nakamura T, Sakamoto N, Tsuchiya K, Yagita H., Watanabe M.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. 296
  • 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
  • Peer Reviewed
• [Journal Article] Requirement of Notch activation during regeneration of the intestin al 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
  • 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): 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
  • 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, Okamoto R, Tsuchiya K, Nakamura T, Sakamoto N, Akiba H, Okumura K, Yagita H, Watanabe M
  • Journal Title: J Immunol (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, Kamata M, Hisamatsu T, Watanabe M, Hibi T
  • Journal Title: Curr Opin Gastroenterol (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 (2009)
  • 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] 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, N emoto Y, Okamoto R, Tsuchiya K, Totsuka T, Sakamoto N, Akira S, Watanabe M
  • Journal Title: J Iinmunol 180 Pages: 5291-5298
  • 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, N emoto Y, Okamoto R, Tsuchiya K, Totsuka T, Sakamoto N, Watanabe M
  • Journal Title: Eur J Immunol 38 Pages: 1264-1274
  • Peer Reviewed
• [Presentation] Long-lived Colitogenic CD4+ Memory T Cells can be Maintained Outside the Intestine in the Absence of Commesal Bacteria (2009)
  • Author(s): 根本泰宏、金井隆典、松本敏、渡辺守
  • Organizer: Japan & US Collaboration Conference in Gastroenterology
  • Place of Presentation: 東京
  • Year and Date: 2009-11-20
• [Presentation] 腸内細菌から直接的自然免疫と抗原刺激を受ける炎症性腸疾患メモリ-CD4+T細胞の維持機構 (2009)
  • Author(s): 根本泰宏、金井隆典、渡辺守
  • Organizer: 日本消化器病学会パネルディスカッション
  • Place of Presentation: 東京
  • Year and Date: 2009-10-15
• [Presentation] 炎症性腸疾患治療標的としてのIL-7高産生細胞の同定 (2009)
  • Author(s): 根本泰宏、金井隆典、渡辺守
  • Organizer: 日本消化器免疫学会総会シンポジウム
  • Place of Presentation: 松山市
  • Year and Date: 2009-07-24
• [Presentation] Long-lived Colitogenic CD4+ Memory T Cells Residing Outside the Intestine Participate in the Perpetuation of Chronic Colitis (2009)
  • Author(s): 根本泰宏、金井隆典、渡辺守
  • Organizer: Intemational Congress of Mucosal Immunology
  • Place of Presentation: ボストン
  • Year and Date: 2009-07-07
• [Presentation] IL-17を標的とした腸炎惹起性メモリ-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 CD4IT Cells by increased granulopoiesis (2008)
  • Author(s): Nemoto T, Y, Kanai T, Tohda S, Tptsuka T, Okamoto R, Isuchiya K, Fukuda T, Yagita H, and Watanabe M
  • Organizer: 109^<th>Annual meeting of the AGA Tnstitute
  • Place of Presentation: San Diego, CA
  • Year and Date: 2008-05-20