機能的粘膜バリア機構破綻による慢性腸炎発症過程の解析

2023 Fiscal Year Annual Research Report

• Project/Area Number: 23H02888
• Allocation Type: Single-year Grants
• 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): 藤井 俊光 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 (30547451)
• Project Period (FY): 2023-04-01 – 2026-03-31
• 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粘膜バリア機構の維持によって制御され、その破綻がIBDの本態となる」という独自の概念や知見を基盤として、独自の腸炎モデル、新規バイオセンサーおよび生体イメージング技術等、我々がこれまでに樹立してきた技術を融合し、これまで理解し得なかったGALTにおける免疫寛容の誘導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）定常状態の野生型C57BL6マウス(WT)の脾臓、肝臓、腸間膜リンパ節といった二次リンパ組織、あるいはパイエル板、粘膜固有層リンパ球、腸上皮間リンパ球などのGALTから各免疫担当細胞を単離し、マクロファージや樹状細胞といった抗原提示細胞をさらなるその他の表面マーカーによって各サブセットに分取することに成功した。２）これらの各サブセットにおけるIL-12、IL-4、IL-6、TGF-bなどの発現を解析したところ、各細胞系統に異なる発現パターンを呈するものが混在することを見出した。３）これを受け、IL-10やTGF-bを発現する集団とそれ以外の各集団の比率を細胞系統ごとに解析したところ、免疫寛容の誘導に大きく関わることが推測される複数の集団を見出した。４）さらに生体内におけるこれらの集団に着目し、こうした細胞とT細胞との接触や細胞径を共焦点顕微鏡下で確認することに成功した。
これらの研究成果は、定常時の腸管粘膜における免疫寛容状態の客観的な機能的解析がin vitroおよびin vivoで可能であることを示唆する。さらに現在、この免疫寛容メカニズムの詳細な生化学・細胞生物学的解析、生体イメージング観察、および腸炎発症時における同様の観察準備を進めている。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

腸管粘膜の免疫寛容や免疫賦活の調節は、抗原提示細胞や粘膜バリア機構によって制御されていることが根幹にあり、GALTにおける正常な免疫寛容誘導の破綻がIBDの本態となる可能性について着目しているが、今回我々は免疫寛容状態に深く関わることが推測される抗原提示細胞サブセットを、in vitro、ex vivoおよびin vivoで客観的に観察、評価できたことは大きな成果であるといえる。

Strategy for Future Research Activity

今後はin vitroおよびex vivoにおける細胞間クロストークの分子メカニズムに着目し、これをさらに詳細に解析するために分子生物学的解析や共焦点顕微鏡下での生体イメージング観察、またin vivo実験系では独自の腸炎モデルにおける臨床および病理学的解析、フローサイトメトリー、サイトカイン測定、また免疫組織染色などを行う予定である。

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] Single cell analysis revealed that two distinct, unique CD4+ T cell subsets were increased in the small intestinal intraepithelial lymphocytes of aged mice. (2024)
  • Author(s): Yuki Yonemoto, Yasuhiro Nemoto, Ryo Morikawa, Nana Shibayama, Shigeru Oshima, Takashi Nagaishi, Tomohiro Mizutani, Go Ito, Satoru Fujii, Ryuichi Okamoto.
  • Journal Title: Frontiers in Immunology. Volume: 15 Pages: e1340048
  • DOI: 10.3389/fimmu.2024.1340048.
  • Peer Reviewed
• [Journal Article] Combination of leucine-rich alpha-2 glycoprotein and fecal markers detect Crohn’s disease activity confirmed by balloon-assisted enteroscopy. (2024)
  • Author(s): Kawamoto Ami, Takenaka Kento, Hibiya Shuji, Kitazume Yoshio, Shimizu Hiromichi, Fujii Toshimitsu, Saito Eiko, Ohtsuka Kazuo, Okamoto Ryuichi.
  • Journal Title: Intestinal Research Volume: 22 Pages: 65-74
  • DOI: 10.5217/ir.2023.00092
  • Peer Reviewed / Open Access
• [Journal Article] IgA による腸内細菌叢調節と腸管粘膜防御の検証. (2023)
  • Author(s): 永石宇司.
  • Journal Title: 東京医科歯科大学医科同窓会会報. Volume: 301 Pages: 23
• [Journal Article] 炎症性腸疾患モデルにおける炎症性発癌機構の解析. (2023)
  • Author(s): 井上忠彦, 永石宇司.
  • Journal Title: 細胞. Volume: 55 Pages: 1005-1009
• [Journal Article] IgAによる回腸免疫恒常性の維持. (2023)
  • Author(s): 永石宇司, 井上忠彦, 伏見萌音, 山田大貴, 岡本隆一, 安達貴弘.
  • Journal Title: 消化器病学サイエンス. Volume: 7 Pages: 86-89
• [Journal Article] 慢性下痢の原因となる薬剤. (2023)
  • Author(s): 山田大貴, 永石宇司.
  • Journal Title: IBD Research. Volume: 17 Pages: 112-115
• [Journal Article] A case of venous stasis colitis possibly caused by eplerenone. (2023)
  • Author(s): Eiko Saito, Kazuo Ohtsuka, Ami Kawamoto, Toshimitsu Fujii, Kento Takenaka, Shuji Hibiya, Hiromichi Shimizu, Masakazu Nagahori, Shohei Tomii, Ryuichi Okamoto.
  • Journal Title: Clinical Journal of Gastroenterology Volume: 16 Pages: 69-72
  • DOI: 10.1007/s12328-022-01722-5
  • Peer Reviewed
• [Journal Article] Transmural Remission Characterized by High Biologic Concentrations Demonstrates Better Prognosis in Crohn’s Disease. (2023)
  • Author(s): Kento Takenaka, Ami Kawamoto, Yoshio Kitazume, Toshimitsu Fujii, Yumi Udagawa, Hiromichi Shimizu, Shuji Hibiya, Masakazu Nagahori, Kazuo Ohtsuka, Mamoru Watanabe, Ryuichi Okamoto.
  • Journal Title: Journal of Crohn's and Colitis Volume: 17 Pages: 855-862
  • DOI: 10.1093/ecco-jcc/jjac185
  • Peer Reviewed
• [Journal Article] Serum Leucine-Rich α2 Glycoprotein: A Novel Biomarker for Transmural Inflammation in Crohn's Disease. (2023)
  • 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: American Journal of Gastroenterology Volume: 118 Pages: 1028-1035
  • DOI: 10.14309/ajg.0000000000002127
  • Peer Reviewed
• [Journal Article] Association of ulcerative colitis symptom severity and proctocolectomy with multidimensional patient-reported outcomes: a cross-sectional study. (2023)
  • Author(s): Katsuyoshi Matsuoka, Hajime Yamazaki, Masakazu Nagahori, Taku Kobayashi, Teppei Omori, Yohei Mikami, Toshimitsu Fujii, Shinichiro Shinzaki, Masayuki Saruta, Minoru Matsuura, Takayuki Yamamoto, Satoshi Motoya, Toshifumi Hibi, Mamoru Watanabe, Jovelle Fernandez, Shunichi Fukuhara, Tadakazu Hisamatsu.
  • Journal Title: Journal of Gastroenterology Volume: 58 Pages: 751-765
  • DOI: 10.1007/s00535-023-02005-7
  • Peer Reviewed
• [Journal Article] Diagnosis and Clinical Features of Perianal Lesions in Newly Diagnosed Crohn’s Disease: Subgroup Analysis from Inception Cohort Registry Study of Patients with Crohn’s Disease (iCREST-CD). (2023)
  • Author(s): Takayuki Yamamoto, Hiroshi Nakase, Kenji Watanabe, Shinichiro Shinzaki, et al.
  • Journal Title: Journal of Crohn's and Colitis Volume: 17 Pages: 1193-1206
  • DOI: 10.1093/ecco-jcc/jjad038
  • Peer Reviewed
• [Journal Article] Efficacy and safety of risankizumab for Crohn's disease in patients from Asian countries: a post hoc subanalysis of the global phase 3 ADVANCE, MOTIVATE, and FORTIFY studies. (2023)
  • Author(s): Gao Xiang, Fujii Toshimitsu, Ye Byong Duk, Chou Jen‐Wei, Sugimoto Ken, Cao Qian, Kligys Kristina, Murakoshi Kaoru, Teng Dennis, Zhang Yafei, Nakase Hiroshi.
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: 39 Pages: 55-65
  • DOI: 10.1111/jgh.16358
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Maintenance Risankizumab Sustains Induction Response in Patients with Crohn’s Disease in a Randomized Phase 3 Trial. (2023)
  • Author(s): Ferrante Marc, Irving Peter M, Abreu Maria T, Axler Jeffrey, Gao Xiang, Cao Qian, Fujii Toshimitsu, Rausch Astrid, Torres Joana, Neimark Ezequiel, Song Alexandra, Wallace Kori, Kligys Kristina, Berg Sofie, Liao Xiaomei, Zhou Qing, Kalabic Jasmina, Feagan Brian, Panaccione Remo.
  • Journal Title: Journal of Crohn's and Colitis Volume: 18 Pages: 416-423
  • DOI: 10.1093/ecco-jcc/jjad168
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] COVID-19 severity is associated with the risk of gastrointestinal bleeding. (2023)
  • Author(s): Hibiya Shuji, Fujii Takashi, Fujii Toshimitsu, Suzuki Shinji, Kondo Mayumi, Ooka Shinya, Furumoto Yohei, Azuma Seishin, Tanaka Kei, Kurata Hitoshi, Tanaka Shohei, Kurosaki Masayuki, Nagayama Kazuyoshi, Kusano Fumihiko, Iizuka Yasuhiro, Kawamura Takahiro, et al.
  • Journal Title: BMJ Open Gastroenterology Volume: 10 Pages: e001199
  • DOI: 10.1136/bmjgast-2023-001199
  • Peer Reviewed / Open Access
• [Journal Article] 【炎症性腸疾患に対する検査法の進歩】Cross-sectional imagingとしてのMRIとtransmural healing. (2023)
  • Author(s): 藤井俊光, 岡本隆一.
  • Journal Title: 日本消化器病学会雑誌 Volume: 120 Pages: 888-897
  • Peer Reviewed
• [Journal Article] 【小腸画像診断のトピックス】MR enterography. (2023)
  • Author(s): 竹中健人, 藤井俊光, 大塚和朗, 岡本隆一.
  • Journal Title: 胃と腸 Volume: 58 Pages: 1491-1498
  • Peer Reviewed
• [Journal Article] 【潰瘍性大腸炎に対する同種同効薬を使い分ける!】JAK阻害薬はすべて同じ使い方か? (2023)
  • Author(s): 藤井俊光.
  • Journal Title: IBD Research Volume: 17 Pages: 267-274
  • Peer Reviewed
• [Presentation] A pathogenic role of activated mucosal-associated invariant T cells in an animal model of Inflammatory Bowel Disease. (2024)
  • Author(s): Yusuke Yasutomi, Asako Chiba, Keiichi Haga, Goh Murayama, Ayako Makiyama, Akihito Nagahara, Takashi Nagaishi, Sachiko Miyake.
  • Organizer: Annual meeting of European Crohn's and Colitis Organisation 2024.
  • Int'l Joint Research
• [Presentation] Downregulated apelin expression in T cells in the setting of chronic colitis. (2024)
  • Author(s): Tadahiko Inoue, Mone Fushimi, Daiki Yamada, Taro Watabe, Mamoru Watanabe, Ryuichi Okamoto, Takashi Nagaishi.
  • Organizer: Annual meeting of European Crohn's and Colitis Organisation 2024.
  • Int'l Joint Research
• [Presentation] B cell receptor signaling-mediated activation in lymphoid tissues is regulated by the long isoform of CEACAM1. (2024)
  • Author(s): Tadahiko Inoue, Mone Fushimi, Naoya Tsugawa, Daiki Yamada, Taro Watabe, Mamoru Watanabe, Ryuichi Okamoto, Takahiro Adachi, Richard S. Blumberg, Takashi Nagaishi.
  • Organizer: Annual meeting of Japanese Society of Immunology 2024.
  • Int'l Joint Research
• [Presentation] APL downregulation in T cells in an animal model of chronic colitis. (2024)
  • Author(s): Mone Fushimi, Tadahiko Inoue, Daiki Yamada, Taro Watabe, Mamoru Watanabe, Ryuichi Okamoto, Takashi Nagaishi.
  • Organizer: Annual meeting of Japanese Society of Immunology 2024.
  • Int'l Joint Research
• [Presentation] Post-marketing surveillance of tofacitinib in patients with ulcerative colitis in Japan: a final report of effectiveness and safety data. (2024)
  • Author(s): Katsuyoshi Matsuoka, Satoshi Motoya, Takayuki Yamamoto, Minoru Matsuura, Toshimitsu Fujii, Shinichiro Shinzaki, Yohei Mikami, Shoko Arai, Junichi Oshima, Yutaka Endo, Hirotoshi Yuasa, Masato Hoshi, Keiko Sato, Tadakazu Hisamatsu.
  • Organizer: 19th Congress of ECCO
  • Int'l Joint Research
• [Presentation] Clinical features and surgical necessity rate of fistulisingperianal disease in newly diagnosed patients with Crohn's disease: Interim analysis of inception cohort registry study of patients with Crohn's disease (iCREST-CD). (2024)
  • Author(s): N.Takatsu, T.Yamamoto, H.Nakase, S.Shinzaki, K.Watanabe, T.Fujii, R.Okamoto, K.Matsuoka, A.Yamada, R.Kunisaki, M.Matsuura, H.Shiga, S.Bamba, Y.Mikami, T.Shimoyama, S.Motoya, T.Torisu, T.Kobayashi, N.Ohmiya, M.Saruta, S.Yoshigoe, Y.Murata, T.Hisamatsu.
  • Organizer: 19th Congress of ECCO
  • Int'l Joint Research
• [Presentation] Ozanimod as a once-daily oral therapy for Japanese patients with ulcerative colitis: results from the induction period of a phase 2/3 study (J-True North). (2024)
  • Author(s): Katsuyoshi Matsuoka, Hiroshi Nakase, Toshimitsu Fujii, Tadakazu Hisamatsu, Yasuo Suzuki, Mamoru Watanabe, Yoko Uchikawa, Shoichiro Goto, Go Fujimoto, Changliang Zhang, Toshifumi Hibi.
  • Organizer: 19th Congress of ECCO
  • Int'l Joint Research
• [Presentation] APL downregulation in T cells in the setting of chronic colitis. (2023)
  • Author(s): Mone Fushimi, Tadahiko Inoue, Daiki Yamada, Taro Watabe, Mamoru Watanabe, Ryuichi Okamoto, Takashi Nagaishi.
  • Organizer: United European Gastroenterology Week 2024.
  • Int'l Joint Research
• [Presentation] Corticosteroid-Sparing Effect of Upadacitinib in Patients With Moderately to Severely Active Crohn’s Disease. (2023)
  • Author(s): Marla C. Dubinsky, Geert D’Haens, Olivier Dewit, Pascal Juillerat, Remo Panaccione, Toshimitsu Fujii, Ana P Lacerda, Elena Dubcenco, Samuel Anyanwu, Chirag Doshi, John Liu, Andrew Garrison, Edward V Loftus Jr.
  • Organizer: ACG 2023 - American College of Gastroenterology
  • Int'l Joint Research
• [Presentation] The Efficacy of Induction Treatment With Guselkumab in Patients with Moderately to Severely Active Ulcerative Colitis: Phase 3 QUASAR Induction Study Results at Week 12 by Prior Advanced Therapy History. (2023)
  • Author(s): B. Bressler, L. Peyrin-Biroulet, J.R. Allegretti, K.G. Huang, M. Germinaro, N. Shipitofsky, Y. Miao, H. Zhang, M. Bortlik, T. Hlavaty, T. Fujii, B.G. Feagan, B.E. Sands, A. Dignass on behalf of the QUASAR Investigators.
  • Organizer: ACG 2023 - American College of Gastroenterology
  • Int'l Joint Research
• [Presentation] Corticosteroid discontinuation and clinical outcomes in patients with moderately to severely active Crohn’s disease treated with upadacitinib. (2023)
  • Author(s): Marla C. Dubinsky, Geert D’Haens, Olivier Dewit, Pascal Juillerat, Remo Panaccione, Toshimitsu Fujii, Ana P Lacerda, Elena Dubcenco, Samuel Anyanwu, Chirag Doshi, Madhuja Mallick, Andrew Garrison, John Liu, Edward V Loftus Jr.
  • Organizer: SGG Swiss congress 2023
  • Int'l Joint Research
• [Presentation] Corticosteroid Discontinuation and Clinical Outcomes in Patients With Moderately to Severely Active Crohn’s Disease Treated With Upadacitinib. (2023)
  • Author(s): Marla C. Dubinsky, Geert D’Haens, Olivier Dewit, Pascal Juillerat, Remo Panaccione, Toshimitsu Fujii, Ana P. Lacerda, Elena Dubcenco, Samuel Anyanwu, Chirag Doshi, Madhuja Mallick, Andrew Garrison, John Liu, Edward V. Loftus Jr.
  • Organizer: DDW2023 米国消化器病学会
  • 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. (2023)
  • Author(s): Marc Ferrante, Qian Cao, Toshimitsu Fujii, Astrid Rausch, Ezequiel Neimark, Alexandra Song, Kori Wallace, Kristina Kligys, Qing Zhou, Jasmina Kalabic, Brian Feagan.
  • Organizer: DDW2023 米国消化器病学会
  • Int'l Joint Research
• [Presentation] Severe COVID-19 is associated with risk of lower gastrointestinal bleeding. (2023)
  • Author(s): Shuij Hibiya, Takashi Fujii, Toshimitsu Fujii, Kazuo Ohtsuka, Ryuichi Okamoto.
  • Organizer: UEG Week 2023 欧州消化器病学会
  • Int'l Joint Research
• [Presentation] COMBINING LEUCINE-RICH ALPHA-2 GLYCOPROTEIN AND FAECAL BIOMARKERS FOR ACCURATE MONITORING OF SMALL BOWEL ACTIVITY IN CROHN’S DISEASE. (2023)
  • Author(s): A. Kawamoto, K. Takenaka, S. Hibiya, Y. Kitazume, K. Ito, H. Shimizu, T. Fujii, E. Saito, K. Ohtsuka, R. Okamoto.
  • Organizer: UEG Week 2023 欧州消化器病学会
  • Int'l Joint Research
• [Presentation] DUAL THERAPY WITH CAROTEGRAST (AJM300: ORAL α4 INTEGRIN ANTAGONIST) AND BIOLOGICS FOR REFRACTORY ULCERATIVE COLITIS. (2023)
  • Author(s): T. Fujii , S. Hibiya , H. Shimizu , A. Kawamoto , K. Takenaka , E. Saito , M. Nagahori , K. Ohtsuka , R. Okamoto.
  • Organizer: UEG Week 2023 欧州消化器病学会
  • Int'l Joint Research
• [Presentation] Efficacy of Induction Upadacitinib Therapy in East Asian Patients With Moderately to Severely Active Crohn’s Disease. (2023)
  • Author(s): Minhu Chen, Xiang Gao, Kenji Watanabe, Toshimitsu Fujii, Jae Hee Cheon, Shu-Chen Wei, Dennis Teng, Ana P Lacerda, Valencia P Remple, Hiroshi Nakase.
  • Organizer: UEG Week 2023 欧州消化器病学会
  • Int'l Joint Research
• [Presentation] The Efficacy of Induction Treatment With Guselkumab in Patients with Moderately to Severely Active Ulcerative Colitis: Phase 3 QUASAR Induction Study Results at Week 12 by Prior Advanced Therapy History. (2023)
  • Author(s): B. Bressler, L. Peyrin-Biroulet, J.R. Allegretti, K.G. Huang, M. Germinaro, N. Shipitofsky, Y. Miao, H. Zhang, M. Bortlik, T. Hlavaty, T. Fujii, B.G. Feagan, B.E. Sands, A. Dignass on behalf of the QUASAR Investigators.
  • Organizer: UEG Week 2023 欧州消化器病学会
  • Int'l Joint Research