Regulation of lipid-reactive lymphocytes for IBD treatment

2019 Fiscal Year Annual Research Report

• Project/Area Number: 17K09372
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 藤井 俊光 東京医科歯科大学, 医学部附属病院, 助教 (30547451)
• Co-Investigator(Kenkyū-buntansha): 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) ; 渡辺 守 東京医科歯科大学, 高等研究院, 特別栄誉教授 (10175127)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: 免疫 / 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「食餌や腸内細菌由来の脂質抗原と腸管上皮細胞におけるCD1ｄ発現に着目したこの機構の調節がIBDの治療に繋がる」という独自の概念や知見を基盤として、腸上皮細胞における脂質抗原提示の調節による脂質応答性リンパ球制御の可能性について追及している。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）マウス腸管組織から単離した腸管上皮細胞を初代培養し、ここに同様のウイルスベクターGFP-RVおよびDsRed-RV、また阻害剤を使用する実験系を樹立させることを試みたが、これらの使用は困難であった。２）しかし予定の計画に追加して、代替え策としてマウス腸管組織から上皮細胞株を樹立し、共焦点顕微鏡下でCD1ｄの発現、小胞体、リソソームなどの観察を行うことは可能であった。３）またマウスから単離した脂質応答性リンパ球を前述した上皮細胞株と共培養する条件を見出した。４）さらにこの混合培養によって培養上清中のサイトカイン産生を測定できることが確認された。これらの研究成果は上記の条件下における腸上皮細胞株による抗原提示機能をex vivoで詳細に解析できる可能性が保証され、またその条件下における免疫学的解析が可能であることを示唆する。さらに現在、これらの細胞を用いた生化学的解析や機能的解析にむけて、その条件検討を進めている。さらに、in vivo実験系では遺伝子改変動物における疾患モデルの誘導とその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現在試みている。

Research Products

• [Journal Article] Development and validation of a deep neural network for accurate evaluation of endoscopic images from patients with ulcerative colitis. (2020)
  • Author(s): Kento Takenaka , Kazuo Ohtsuka , Toshimitsu Fujii , Mariko Negi , Kohei Suzuki , Hiromichi Shimizu , Shiori Oshima , Shintaro Akiyama , Maiko Motobayashi , Masakazu Nagahori , Eiko Saito , Katsuyoshi Matsuoka , Mamoru Watanabe
  • Journal Title: Gastroenterology Volume: Epub ahead of print Pages: in press
  • DOI: 10.1053/j.gastro.2020.02.012.
  • Peer Reviewed
• [Journal Article] CD8αα+ T cells show amoeboid shape and frequent morphological change in vitro, and localize to small intestinal intraepithelial region in vivo. (2020)
  • Author(s): Yuria Takei, Yasuhiro Nemoto, Ryo Morikawa, Shohei Tanaka, Shigeru Oshima, Takashi Nagaishi, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Mamoru Watanabe.
  • Journal Title: Biochem Biophys Res Commun. Volume: 523 Pages: 328-335
  • DOI: 10.1016/j.bbrc.2019.12.021.
  • Peer Reviewed / Open Access
• [Journal Article] High-fat diet-derived free fatty acids impair the intestinal immune system and increase sensitivity to intestinal epithelial damage. (2020)
  • Author(s): Shohei Tanaka, Yasuhiro Nemoto, Yuria Takei, Ryo Morikawa, Shigeru Oshima, Takashi Nagaishi, Ryuichi Okamoto, Kiichiro Tsuchiya, Tetsuya Nakamura, Susanne Stutte, Mamoru Watanabe.High-fat diet-derived free fatty acids impair the intestinal immune system and increase sensitivity to intestinal epithelial damage.
  • Journal Title: Biochem Biophys Res Commun. Volume: 522 Pages: 971-977
  • DOI: 10.1016/j.bbrc.2019.11.158.
  • Peer Reviewed / Open Access
• [Journal Article] Receptor-interacting protein kinase 3 (RIPK3) inhibits autophagic flux during necroptosis in intestinal epithelial cells. (2020)
  • Author(s): Kana Otsubo, Chiaki Maeyashiki, Yoichi Nibe, Akiko Tamura, Emi Aonuma, Hiroki Matsuda, Masanori Kobayashi, Michio Onizawa, Yasuhiro Nemoto, Takashi Nagaishi, et al.
  • Journal Title: FEBS Lett. Volume: 594 Pages: 1586-1595
  • DOI: 10.1002/1873-3468.13748.
  • Peer Reviewed / Open Access
• [Journal Article] Indolent T cell lymphoproliferative disorder with villous atrophy in small intestinediagnosed by single-balloon enteroscopy. (2019)
  • Author(s): Takashi Nagaishi, Daiki Yamada, Kohei Suzuki, Ryosuke Fukuyo, Eiko Saito, Masayoshi Fukuda, Taro Watabe, Naoya Tsugawa, Kengo Takeuchi, Kouhei Yamamoto, Ayako Arai, Kazuo Ohtsuka, Mamoru Watanabe.
  • Journal Title: Clin J Gastroenterol. Volume: 12 Pages: 434-440
  • DOI: 10.1007/s12328-019-00971-1.
  • Peer Reviewed / Open Access
• [Journal Article] Small bowel healing detected by endoscopy in patients with Crohn's disease after treatment with antibodies against tumor necrosis factor. (2019)
  • Author(s): Kento Takenaka , Toshimitsu Fujii , Kohei Suzuki , Hiromichi Shimizu , Maiko Motobayashi , Shuji Hibiya , Eiko Saito , Masakazu Nagahori , Mamoru Watanabe , Kazuo Ohtsuka
  • Journal Title: J Gastroenterol Hepatol. Volume: 18 Pages: 1545-1552
  • DOI: 10.1016/j.cgh.2019.08.024.
• [Journal Article] Crohn disease: a 5-Point MR enterocolonography classification using enteroscopic findings. (2019)
  • Author(s): Yoshio Kitazume, Tomoyuki Fujioka, Kento Takenaka, Jun Oyama, Kazuo Ohtsuka, Toshimitsu Fujii, Ukihide Tateishi
  • Journal Title: AJR Am J Roentgenol. Volume: 212 Pages: 67-76
  • DOI: 10.2214/AJR.17.18897.
• [Journal Article] Predictors of mucosal healing during induction therapy in patients with acute moderate-to-severe ulcerative colitis. (2019)
  • Author(s): Maiko Motobayashi, Katsuyoshi Matsuoka, Kento Takenaka, Toshimitsu Fujii, Masakazu Nagahori, Kazuo Ohtsuka, Fumihiko Iwamoto, Kiichiro Tsuchiya, Mariko Negi, Yoshinobu Eishi, Mamoru Watanabe
  • Journal Title: J Gastroenterol Hepatol. Volume: 34 Pages: 1004-1010
  • DOI: 10.1111/jgh.14565.
• [Presentation] B cell receptor signaling in lymphoid tissues may be regulated by CEACAM1. (2020)
  • Author(s): Takashi Nagaishi, Naoya Tsugawa, Daiki Yamada, Taro Watabe, Michio Onizawa, Mamoru Watanabe.
  • Organizer: European Crohn’s and Colitis Organization 2020
  • Int'l Joint Research
• [Presentation] IBDモデルにおける腸管二次リンパ組織の機能解析. (2020)
  • Author(s): 永石宇司、渡部太郎、渡辺 守.
  • Organizer: 日本応用酵素協会「全身性炎症疾患の病因・病態に関する研究助成」 第9回研究発表会
• [Presentation] IgA-deficiency causes spontaneous enteritis. (2019)
  • Author(s): Takahiro Adachi, Taro Watabe, Takashi Nagaishi, Mamoru Watanabe, Hajime Karasuyama, Soichiro Yoshikawa.
  • Organizer: 第48回日本免疫学会学術集会
  • Int'l Joint Research
• [Presentation] BCR signaling in the activated B cells may be regulated by the long isoform of Ceacam1. (2019)
  • Author(s): Naoya Tsugawa, Takashi Nagaishi, Daiki Yamada, Yudai Kojima, Taro Watabe, Shuang Wang, Michio Onizawa, Takahiro Adachi, Mamoru Watanabe.
  • Organizer: 第48回日本免疫学会学術集会
  • Int'l Joint Research
• [Presentation] 培養腸上皮幹細胞を用いた炎症性腸疾患に対する再生医療の開発. (2019)
  • Author(s): 岡本隆一、清水寛路、鈴木康平、高橋純一、川井麻央、平栗優衣、竹岡さや香、杉原ハディ優樹、永田紗矢香、竹中健人、齋藤詠子、福田将義、藤井俊光、長堀正和、油井史郎、土屋輝一郎、大塚和朗、渡辺 守
  • Organizer: 厚生労働科学研究費 難治性疾患政策研究事業 「難治性炎症性腸管障害に関する調査研究」令和元年度 第1回総会
• [Presentation] Analysis of ileocecal immune response in an animal model of colitis. (2019)
  • Author(s): Daiki Yamada, Takashi Nagaishi, Taro Watabe, Naoya Tsugawa, Yudai Kojima,Nisha Jose, Akinori Hosoya, Takahiro Adachi, Mamoru Watanabe.
  • Organizer: International Congress of Mucosal Immunology 2019
  • Int'l Joint Research
• [Presentation] Analysis of APL expression in an animal model of chronic colitis. (2019)
  • Author(s): Takashi Nagaishi, Yudai Kojima, Taro Watabe, Naoya Tsugawa, Daiki Yamada, Nisha Jose, Akinori Hosoya, Masahiro Suzuki, Michio Onizawa, Mamoru Watanabe.
  • Organizer: Federation of Clinical Immunology Societies 2019
  • Int'l Joint Research
• [Presentation] APL downregulation in an animal model of chronic colitis. (2019)
  • Author(s): Daiki Yamada, Takashi Nagaishi, Yudai Kojima, Taro Watabe, Naoya Tsugawa, Nisha Jose, Akinori Hosoya, Masahiro Suzuki, Michio Onizawa, Mamoru Watanabe.
  • Organizer: Asian Organization of Crohn’s and Colitis 2019
  • Int'l Joint Research
• [Presentation] Small bowel endoscopic healing of Crohn’s disease treated with anti-TNF antibodies. (2019)
  • Author(s): Kento Takenaka, Kazuo Ohtsuka, Toshimitsu Fujii, Kohei Suzuki, Hiromichi Shimizu, Maiko Motobayashi, Shuji Hibiya, Eiko Saito, Masakazu Nagahori, Mamoru Watanabe
  • Organizer: Asian Organization of Crohn’s and Colitis 2019
  • Int'l Joint Research
• [Presentation] The clinical efficacy of ustekinumab (UST) in patients with Crohn’s disease (CD). (2019)
  • Author(s): Eiko Saito, Kohei Suzuki, Shuji Hibiya, Maiko Motobayashi, Kento Takenaka, Nobukatsu Horita, Hiromichi Shimizu, Michio Onizawa, Toshimitsu Fujii, Masakazu Nagahori, Kazuo Ohtsuka, Mamoru Watanabe
  • Organizer: Asian Organization of Crohn’s and Colitis 2019
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 炎症性腸疾患の治療方法およびそれに用いるための医薬組成物 (2019)
  • Inventor(s): 永石宇司
  • Industrial Property Rights Holder: 永石宇司
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-554239