腸管免疫寛容誘導と炎症性腸疾患発症過程の解析

2022 Fiscal Year Annual Research Report

• Project/Area Number: 20H03658
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 永石 宇司 東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座准教授 (60447464)
• Co-Investigator(Kenkyū-buntansha): 長堀 正和 東京医科歯科大学, 東京医科歯科大学病院, 准教授 (60420254)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 免疫学 / 腸管免疫 / 消化器病学 / 炎症性腸疾患

Outline of Annual Research Achievements

本研究は申請者らがこれまで見出してきた「腸管粘膜の免疫恒常性はGALTにおける正常な免疫寛容の誘導によって制御され、その異常がIBDの本態となる」という独自の概念や知見を基盤として、新規バイオセンサーおよび生体イメージング技術等、我々が独自に樹立している技術を融合し、これまで理解し得なかったGALTにおける免疫応答の調節機構について追求している。その結果、本研究では当該研究期間に以下のような成果が得られた。
１）野生型C57BL6マウス(WT)にDSS腸炎を誘発したところ、抗原提示細胞のTNFやIFN-g発現の上昇を確認することは困難であった。一方、TNBS腸炎やOxazolone腸炎を誘発すると、これらを測定する適した条件を見出すことができた。２）WTにTNBS腸炎を誘発し、パイエル板や腸間膜リンパ節など生体内の二次リンパ組織を観察した結果、抗原提示細胞とT細胞との接触や増大を共焦点顕微鏡下で確認することに成功した。３）その上で上記のTNBS腸炎を誘発したマウスの脾臓、腸間膜リンパ節、あるいはパイエル板、粘膜固有層リンパ球などのGALTから分取したマクロファージや樹状細胞といった抗原提示細胞の各サブセットにおいて、IL-10やTGF-bの発現は低下し、IL-12やIL-23などの発現は上昇していることを確認することができた。
これらの研究成果から、定常時のみならず腸炎誘発時の腸管粘膜における抗原提示細胞群の客観的な生化学的、細胞生物学的な解析がin vitroおよびin vivoで可能であることを証明した。さらに現在、こうした実験腸炎モデル誘発時における抗原提示細胞群やリンパ球の詳細な生化学・細胞生物学的解析、また生体イメージング観察を進めている。

Research Progress Status

令和4年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

令和4年度が最終年度であるため、記入しない。

Research Products

• [Int'l Joint Research] Brigham and Women's Hospital/Harvard Medical School(米国)
  • Country Name: U.S.A.
  • Counterpart Institution: Brigham and Women's Hospital/Harvard Medical School
• [Int'l Joint Research] University of British Columbia(カナダ)
  • Country Name: CANADA
  • Counterpart Institution: University of British Columbia
• [Journal Article] Apelin expression is downregulated in T cells in a murine model of chronic colitis. (2023)
  • Author(s): Yamada D, Kojima Y, Hosoya A, Suzuki M, Watabe T, Inoue T, Tsugawa N, Asakawa T, Yonemoto Y, Onizawa M, Nemoto Y, Oshima S, Shimonaka M, Kuba K, Ishida J, Fukamizu A, Penninger JM, Watanabe M, Okamoto R, Nagaishi T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 647 Pages: 72-79
  • DOI: 10.1016/j.bbrc.2023.01.068.
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Zranb1-mutant mice display abnormal colonic mucus production and exacerbation of DSS-induced colitis. (2022)
  • Author(s): Tamura A, Ito G, Matsuda H, Nibe-Shirakihara Y, Hiraoka Y, Kitagawa S, Hiraguri Y, Nagata S, Aonuma E, Otsubo K, Nemoto Y, Nagaishi T, Watanabe M, Okamoto R, Oshima S.
  • Journal Title: Biochem Biophys Res Commun. Volume: 628 Pages: 147-154
  • DOI: 10.1016/j.bbrc.2022.08.046.
  • Peer Reviewed
• [Journal Article] Deep neural network for video colonoscopy of ulcerative colitis: a cross-sectional study. (2022)
  • Author(s): Kento Takenaka, Toshimitsu Fujii, Ami Kawamoto, Kohei Suzuki, Hiromichi Shimizu, Chiaki Maeyashiki, Osamu Yamaji, Maiko Motobayashi, Akira Igarashi, Ryoichi Hanazawa, Shuji Hibiya, Masakazu Nagahori , Eiko Saito, Ryuichi Okamoto, Kazuo Ohtsuka, Mamoru Watanabe.
  • Journal Title: Lancet Gastroenterol Hepatol. Volume: 7 Pages: 230-237
  • DOI: 10.1016/S2468-1253(21)00372-1.
  • Peer Reviewed
• [Journal Article] Mucosal healing of small intestinal stricture is associated with improved prognosis post-dilation in Crohn's disease. (2022)
  • Author(s): Shuji Hibiya, Kazuo Ohtsuka, Kento Takenaka, Ami Kawamoto, Yusuke Matsuyama, Yumi Udagawa, Maiko Motobayashi, Hiromichi Shimizu, Toshimitsu Fujii, Eiko Saito, Masakazu Nagahori, Ryuichi Okamoto, Mamoru Watanabe.
  • Journal Title: BMC Gastroenterol. Volume: 22 Pages: 218
  • DOI: 10.1186/s12876-022-02300-2.
  • Peer Reviewed / Open Access
• [Journal Article] Hemorrhagic gastric ulcer in a patient with Behcet's disease successfully treated with infliximab. (2022)
  • Author(s): Shun Fujiwara, Ami Kawamoto, Maiko Motobayashi, Shuji Hibiya, Kento Takenaka, Hiromichi Shimizu, Eiko Saito, Toshimitsu Fujii, Masakazu Nagahori, Daisuke Kawata, Natsuka Umezawa, Tadashi Hosoya, Shinsuke Yasuda, Kazuo Ohtsuka, Ryuichi Okamoto.
  • Journal Title: DEN Open. Volume: 3 Pages: e196.
  • DOI: 10.1002/deo2.196.
  • Peer Reviewed / Open Access
• [Journal Article] Serum Leucine-Rich α2 Glycoprotein: A Novel Biomarker for Transmural Inflammation in Crohn's Disease. (2022)
  • Author(s): Kento Takenaka, Yoshio Kitazume, Ami Kawamoto, Toshimitsu Fujii, Yumi Udagawa, Ryosuke Wanatabe, Hiromichi Shimizu, Shuji Hibiya, Masakazu Nagahori, Kazuo Ohtsuka, Hiroyuki Sato, Akihiro Hirakawa, Mamoru Watanabe, Ryuichi Okamoto.
  • Journal Title: Am J Gastroenterol. Volume: in press Pages: in press
  • DOI: 10.14309/ajg.0000000000002127.
  • Peer Reviewed
• [Presentation] Corticosteroid discontinuation and clinical outcomes in patients with moderately to severely active Crohn's disease treated with upadacitinib. (2023)
  • Author(s): M.C. Dubinsky, G. D’Haens, O. Dewit, P. Juillerat, R. Panaccione, T. Fujii, A.P. Lacerda, E. Dubcenco S. Anyanwu, C. Doshi, M. Mallick, A. Garrison, J. Liu, E.V. Loftus Jr.
  • Organizer: The 18th Annual congress of ECCO 2023
  • Int'l Joint Research
• [Presentation] Selective IgA deficiency induces spontaneous inflammation in the ileum. (2022)
  • Author(s): Nagaishi T, Yamada D, Inoue T, Blumberg RS, Okamoto R, Adachi T.
  • Organizer: The 51st Annual meeting of Japanese Society of Immunology.
  • Int'l Joint Research
• [Presentation] 選択的IgA欠損によって誘発される回腸特異的な免疫異常. (2022)
  • Author(s): 永石宇司, 山田大貴, 渡部太郎, 渡辺守, 岡本隆一, 安達貴弘.
  • Organizer: 第59回 日本消化器免疫学会
• [Presentation] Spontaneous inflammation specifically in the ileum is induced by selective IgA deficiency. (2022)
  • Author(s): Nagaishi T, Yamada D, Adachi T, Watanabe M, Okamoto R, Blumberg RS.
  • Organizer: Annual meeting of American Gastroenterology Association, Digestive Disease Week
  • Int'l Joint Research
• [Presentation] Patients with moderate to severe Crohn’s Disease with and without prior biologic failure demonstrate improved endoscopic outcomes with risankizumab: Results from phase 3 induction and maintenance trials. (2022)
  • Author(s): Ferrante, M.;Cao, Q.;Fujii, T.;Rausch, A.;Neimark, E.;Song, A.;Wallace, K.;Kligys, K.;Zhou, Q.;Kalabic, J.;Feagan, B.G.
  • Organizer: The 17th Annual congress of ECCO 2022
  • Int'l Joint Research
• [Presentation] IMPACT OF INFLAMMATORY BURDEN ON EFFICACY OF UPADACITINIB MAINTENANCE THERAPY IN ULCERATIVE COLITIS: RESULTS FROM THE PHASE 3 U-ACHIEVE STUDY. (2022)
  • Author(s): B. Feagan, J.-F. Colombel, J. Torres, T. Fujii, W. Zhou, X. Yao, Y. Sanchez Gonzalez, D. Ilo, X. Roblin.
  • Organizer: Annual meeting of UEGW 2022
  • Int'l Joint Research
• [Presentation] Clinical and Endoscopic Improvements with Risankizumab Induction and Maintenance Dosing Versus Placebo are Observed Irrespective of Number of Prior Failed Biologics. (2022)
  • Author(s): Marc Ferrante, Laurent Peyrin-Biroulet, Axel Dignass, David T. Rubin, Silvio Danese, Geert D'Haens, Kristina Kligys, Sofie Berg, Jasmina Kalabic, Javier Zambrano, Yafei Zhang, Toshimitsu Fujii, and Remo Panaccione.
  • Organizer: Annual scientific meeting of American College of Gastroenterology 2022
  • Int'l Joint Research