NK細胞サブセットによるクローン病新規治療標的の抽出

2022 Fiscal Year Annual Research Report

• Project/Area Number: 20K08304
• 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)
• Project Period (FY): 2020-04-01 – 2023-03-31
• 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「NK細胞による病原性エフェクターT細胞の調節機構」という独自の概念や知見を基盤として、NK細胞サブセットによる細胞傷害活性を応用した新規治療法開発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）野生型マウス (WT)の脾臓から単離したnaive T細胞をRag欠損マウスに移入してeffecter T細胞を誘導し、これらを既に樹立したT細胞応答性のNK細胞クローンとex vivoで共培養したところ、実際にこれらのクローンがeffecter T細胞を抑制することが確認された。２）その上で、樹立したT細胞応答性のNK細胞クローンの機能を解析したところ、サイトカイン産生能はあまり活性化されていない一方、細胞溶解能や細胞死誘導能は上昇ししており、これによってeffecter T細胞が抑制されていることが示唆された。３）樹立した上記のNK細胞クローンに対しウイルスベクターによる不死化を試みたが、やはり継代は困難であった。しかし特異的リガンドによる刺激によって細胞は増殖し、継代することも可能となった。
これらの研究成果は、生理的条件下における上記NK細胞クローンの免疫学的解析が可能であること、そしてT細胞に影響を与えるNK細胞サブセットの免疫学的機能を通じ、クローン病の新規治療標的分子の抽出が可能であることを示唆している。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を進めている。また実験IBDモデルを用いて、これらの細胞による新規細胞治療の技術開発に向けて、その条件検討を現在準備中である。

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] 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] 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: Clin J Gastroenterol. Volume: 16 Pages: 69-72
  • DOI: 10.1007/s12328-022-01722-5.
  • Peer Reviewed
• [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] Genetic Background of Mesalamine-induced Fever and Diarrhea in Japanese Patients with Inflammatory Bowel Disease (2022)
  • Author(s): Kaoru Suzuki , Yoichi Kakuta , Takeo Naito, Tetsuya Takagawa, Hiroyuki Hanai, Hiroshi Araki, Yu Sasaki, Hirotake Sakuraba, Makoto Sasaki, Tadakazu Hisamatsu, Satoshi Motoya, Takayuki Matsumoto, Motoyuki Onodera, Yoh Ishiguro, Hiroshi Nakase, Akira Andoh, Sakiko Hiraoka, Masaru Shinozaki, Toshimitsu Fujii, et al.
  • Journal Title: Inflamm Bowel Dis . Volume: 28 Pages: 21-31
  • DOI: 10.1093/ibd/izab004.
  • 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] Serum Levels of Infliximab Biosimilar in a Child Delivered From a Mother Treated for Ulcerative Colitis (2022)
  • Author(s): Ami Kawamoto, Toshimitsu Fujii, Ryuji Mitani, Yasuhiro Suzuki, Tsunehito Yauchi, Ryuichi Okamoto
  • Journal Title: Inflamm Bowel Dis. Volume: 28 Pages: 1298-1299
  • DOI: 10.1093/ibd/izac111.
  • Peer Reviewed
• [Journal Article] Characteristics of adult patients newly diagnosed with Crohn's disease: interim analysis of the nation-wide inception cohort registry study of patients with Crohn's disease in Japan (iCREST-CD) (2022)
  • Author(s): Katsuyoshi Matsuoka, Toshimitsu Fujii, Ryuichi Okamoto, Akihiro Yamada, Reiko Kunisaki, Minoru Matsuura, Kenji Watanabe, Hisashi Shiga, Noritaka Takatsu, Shigeki Bamba, Tadakazu Hisamatsu, et al.
  • Journal Title: J Gastroenterol. Volume: 57 Pages: 867-878
  • DOI: 10.1007/s00535-022-01907-2.
  • 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] Motility Mapping Quantification Using the Classical Optical Flow Algorithm for Small Bowel Crohn's Disease: Comparison with Balloon-assisted Enteroscopy Findings (2022)
  • Author(s): Yoshio Kitazume, Kento Takenaka, Kazuo Ohtsuka, Yasuo Ozawa, Koichiro Kimura, Ryosuke Watanabe, Junichi Tsuchiya, Toshimitsu Fujii, Masakazu Nagahori, Mamoru Watanabe, Ukihide Tateishi
  • Journal Title: Magn Reson Med Sci. Volume: - Pages: 2021-0037
  • DOI: 10.2463/mrms.mp.2021-0037.
  • 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] Transmural remission characterized by high biologic concentrations demonstrates better prognosis in Crohn's disease (2022)
  • 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: J Crohns Colitis. Volume: - Pages: -
  • 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 (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: - Pages: -
  • DOI: 10.14309/ajg.0000000000002127.
  • Peer Reviewed
• [Journal Article] 直腸リンパ濾胞過形成様病変から潰瘍性大腸炎の典型像へ進展した1例 (2022)
  • Author(s): 11．大久保 栄高, 藤田 美貴子, 久礼 里江, 藤井 俊光, 冨井 翔平, 根木 真理子, 入江 宏, 畑 啓介.
  • Journal Title: Gastroenterological Endoscopy. Volume: 64 Pages: 262-269
  • Peer Reviewed
• [Journal Article] 最新のIBD病勢モニタリング 画像検査(CT、MRI、腸管超音波、小腸造影)の活用法. (2022)
  • Author(s): 1.藤井 俊光, 岡本 隆一
  • Journal Title: IBD Research. Volume: 16 Pages: 90-96
• [Journal Article] 炎症性腸疾患治療における外科と内科の接点 重症潰瘍性大腸炎に対する治療. (2022)
  • Author(s): 河本 亜美, 藤井 俊光, 岡本 隆一
  • Journal Title: 外科 Volume: 84 Pages: 1054-1059
• [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: 18th Congress of ECCO.
  • 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): 10.Ferrante, M.;Cao, Q.;Fujii, T.;Rausch, A.;Neimark, E.;Song, A.;Wallace, K.;Kligys, K.;Zhou, Q.;Kalabic, J.;Feagan, B.G.
  • Organizer: 17th Congress of ECCO
  • 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: UEGW2022
  • 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: American College of Gastroenterology Annual Scientific Meeting. 2022
  • Int'l Joint Research
• [Presentation] 生物学的製剤無効歴の有無を問わず中等症から重症のクローン病患者においてリサンキズマブによる内視鏡的評価項目の改善が示された：第3相寛解導入・維持試験の結果. (2022)
  • Author(s): 藤井 俊光, Marc Ferrante, Qian Cao, Astrid Rausch, Ezequiel Neimark, Alexandra Song5, Kori Wallace, Kristina Kligys, Qing Zhou, Jasmina Kalabic, Brian Feagan.
  • Organizer: 日本消化器病学会週間JDDW2022
• [Presentation] Infliximab failure難治性潰瘍性大腸炎の病態の後継治療への影響. (2022)
  • Author(s): 齊藤詠子、藤井俊光、大塚和朗、岡本隆一
  • Organizer: 日本消化器病学会週間JDDW2022
• [Presentation] 潰瘍性大腸炎直腸病変に対する局所製剤治療効果の比較検討. (2022)
  • Author(s): 田中将平, 藤井俊光, 中西裕之, 石堂舜, 稲田賢人, 桐野桜, 山下洸司, 延澤翼, 松本浩明, 早川優香, 掛川達矢, 樋口麻友, 高浦健太, 金子俊, 前屋舗千明, 玉城信治, 安井豊, 土谷薫, 黒崎雅之, 泉並木.
  • Organizer: 日本消化器病学会週間JDDW2022
• [Presentation] 再燃寛解型潰瘍性大腸炎に対する最適な治療法の検討. (2022)
  • Author(s): 前屋舖千明, 玉城信治, 石堂舜, 延澤翼, 松本浩明, 樋口麻友, 高浦健, 田中 将平, 安井豊, 藤井俊光, 土谷薫, 中西裕之, 黒崎雅之, 泉並木.
  • Organizer: 日本消化器病学会週間JDDW2022
• [Presentation] IMID(免疫介在性炎症性疾患)におけるT2Tの共通点 炎症性腸疾患におけるタイトコントロールの重要性について. (2022)
  • Author(s): 藤井俊光
  • Organizer: 第50回日本臨床免疫学会総会.
  • Invited
• [Presentation] 内科と外科でクローン病を診る クローン病診療における小腸病変の重要性とTreat to Target. (2022)
  • Author(s): 藤井俊光
  • Organizer: 第77回日本大腸肛門病学会学術集会.
  • Invited
• [Presentation] 中等症から重症のクローン病患者に対するリサンキズマブ導入療法による内視鏡的寛解/改善 の効果：国際共同第3 相導入療法試験（ADVANCE）. (2022)
  • Author(s): 藤井俊光, 村越かおる, 大野浩太, 久松理一.
  • Organizer: 第108回日本消化器内視鏡学会総会.
• [Presentation] 重症潰瘍性大腸炎に対する内科治療と広域内科外科連携の試み. (2022)
  • Author(s): 藤井俊光、藤原俊、岡本隆一.
  • Organizer: 第59回日本腹部救急医学会総会.