Investigation of IL-12/23 pathway in ulcerative colitis

• Project/Area Number: 21K15992
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Shimizu Hiromichi 東京医科歯科大学, 統合研究機構, 助教 (00733875)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2022: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000); Fiscal Year 2021: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 潰瘍性大腸炎 / ILー12／23 / 大腸オルガノイド / IL-12/23 / 抗IL-12/23抗体製剤

Outline of Research at the Start

抗IL-12/23抗体製剤は2020年より本邦の潰瘍性大腸炎治療に導入され、多彩な標的細胞を介して効果を発揮し得る新規製剤である。本研究では研究代表者らが有するオルガノイド共培養系や単一細胞解析系を用い、同製剤効果の全体像を細胞腫横断的に描出することを目的とする。大腸粘膜を構成する免疫担当細胞・間葉系細胞・腸上皮細胞につき1細胞レベルの解析を行い、同製剤が「IL-12/23サイトカイン・ネットワーク」における如何なる細胞種連関を通じて効果の有無が規定されるのかを解明することで、同製剤の治療効果を予測する因子(バイオマーカー)の同定と、それに基づく「迅速な治療の最適化」の達成が期待できる。

Outline of Final Research Achievements

Ulcerative colitis is an idiopathic disease which causes chronic inflammation in colon. For the treatment of ulcerative colitis, anti-inflammatory agents are used such as corticosteroid, immune-modulator and biologic agents. Anti-IL-12/23 anti-body is one of biologic agent blocking specific pro-inflammatory IL-12/23 pathway in colonic tissue. IL-12/23 pathway is a proinflammatory cytokine in ulcerative colitis, interacting numerous other pathways to exacerbates colitis. This study, analyzing patient derived colonic tissue, was aiming to find out in which cells IL-12/23 has any effects, how anti-IL-12/23 antibody reduces and blocks proinflammatory response in colonic tissue, and what is the key biomarkers and/or conditions that determine its treatment efficacy. We underwent single-cell RNA analysis on organoids generated from colonic tissue derived from the patients with ulcerative colitis.

Academic Significance and Societal Importance of the Research Achievements

潰瘍性大腸炎の治療における分子標的薬は、腸管で炎症を引き起こす複雑なサイトカイン・ネットワークの、特異的な経路を阻害して効果を発揮する。しかし、抗IL-12/23抗体製剤が、どの種類の細胞を標的とし、どのように障害された腸粘膜を治癒するのか、そのメカニズムはよくわかっていない。本研究は、患者の臨床情報と患者由来の組織検体の解析を通じて、分子標的薬のひとつ抗IL-12/23抗体製剤の作用メカニズムの解明と、治療予測因子の同定を試みることで、抗IL-12/23抗体製剤の治療効果予測の解明を目標とした研究である。

Research Products

• [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 Issue: 1 Pages: 218-218
  • DOI: 10.1186/s12876-022-02300-2
  • Peer Reviewed / Open Access
• [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 Issue: 3 Pages: 230-237
  • DOI: 10.1016/s2468-1253(21)00372-1
  • Peer Reviewed / Open Access
• [Journal Article] Functional analysis of isoflavones using patient-derived human colonic organoids (2021)
  • Author(s): Tsuchiya Mao、Ito Go、Hama Minami、Nagata Sayaka、Kawamoto Ami、Suzuki Kohei、Shimizu Hiromichi、Anzai Sho、Takahashi Junichi、Kuno Reiko、Takeoka Sayaka、Hiraguri Yui、Sugihara Hady Yuki、Mizutani Tomohiro、Yui Shiro、Oshima Shigeru、Tsuchiya Kiichiro、Watanabe Mamoru、Okamoto Ryuichi
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 542 Pages: 40-47
  • DOI: 10.1016/j.bbrc.2021.01.021
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Notch and TNF-α signaling promote cytoplasmic accumulation of OLFM4 in intestinal epithelium cells and exhibit a cell protective role in the inflamed mucosa of IBD patients (2021)
  • Author(s): Kuno Reiko、Ito Go、Kawamoto Ami、Hiraguri Yui、Sugihara Hady Yuki、Takeoka Sayaka、Nagata Sayaka、Takahashi Junichi、Tsuchiya Mao、Anzai Sho、Mizutani Tomohiro、Shimizu Hiromichi、Yui Shiro、Oshima Shigeru、Tsuchiya Kiichiro、Watanabe Mamoru、Okamoto Ryuichi
  • Journal Title: Biochemistry and Biophysics Reports Volume: 25 Pages: 100906-100906
  • DOI: 10.1016/j.bbrep.2020.100906
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rapid prediction of 1-year efficacy of tofacitinib for treating refractory ulcerative colitis (2021)
  • Author(s): Hiromichi Shimizu, Toshimitsu Fujii, Shuji Hibiya, Maiko Motobayashi, Kohei Suzuki, Kento Takenaka, Eiko Saito, Masakazu Nagahori, Kazuo Ohtsuka, Mamoru Watanabe
  • Journal Title: Intest Res Volume: 19 Issue: 1 Pages: 115-118
  • DOI: 10.5217/ir.2020.00030
  • Peer Reviewed / Open Access
• [Journal Article] Intravenous tacrolimus is a superior induction therapy for acute severe ulcerative colitis compared to oral tacrolimus (2021)
  • Author(s): Hiromichi Shimizu, Toshimitsu Fujii, Kenji Kinoshita, Ami Kawamoto, Shuji Hibiya, Kento Takenaka, Eiko Saito, Masakazu Nagahori, Kazuo Ohtsuka, Mamoru Watanabe, Ryuichi Okamoto
  • Journal Title: BMC Gastroenterol Volume: 21 Issue: 1 Pages: 494-494
  • DOI: 10.1186/s12876-021-02043-6
  • Peer Reviewed / Open Access
• [Presentation] 難治性潰瘍性大腸炎治療におけるトファシチニブの長期使用成績 (2022)
  • Author(s): 青沼 優子、清水 寛路、河本 亜美、日比谷 秀爾、竹中 健人、藤井 俊光、 齊藤 詠子、長堀 正和、大塚 和朗、岡本 隆一
  • Organizer: 第13回日本炎症性腸疾患学会
• [Presentation] 当院における潰瘍性大腸炎に対するフィルゴチニブの治療成績 (2022)
  • Author(s): 清水 寛路、青沼 優子、河本 亜美、日比谷 秀爾、竹中 健人、藤井 俊光、齊藤 詠子、長堀 正和、大塚 和朗、岡本 隆一
  • Organizer: 第13回日本炎症性腸疾患学会