Spatiotemporal analysis and pathogenesis of proinflammatory regulatory T cells in intestinal villi

• Project/Area Number: 19K22624
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 53:Organ-based internal medicine and related fields
• Research Institution: Keio University
• Principal Investigator: SUJINO Tomohisa 慶應義塾大学, 医学部(信濃町), 講師 (40464862)
• Project Period (FY): 2019-06-28 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000); Fiscal Year 2020: ¥2,600,000 (Direct Cost: ¥2,000,000、Indirect Cost: ¥600,000); Fiscal Year 2019: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 2光子顕微鏡 / 腸管免疫 / 制御性T細胞 / 炎症性腸疾患 / ２光子顕微鏡

Outline of Research at the Start

腸管のホメオスタシスの維持には自然リンパ球、マクロファージ、制御性T細胞(regulatory T cells; Treg)などの関与が報告されている。特に炎症抑制能力を有しているTregは消化管の炎症抑制の中心的役割を担っており、炎症の収束及び腸管上皮再生のキープレーヤーである。しかし、炎症性腸疾患患者において、Tregは増加しているにもかかわらず、腸炎が抑制できない相反する結果を有している。腸管炎症において腸管の上皮細胞障害（炎症期）およびその回復期のTreg集積動態に着目し、Treg動態不全と慢性大腸炎発症機序解明について研究を行う。

Outline of Final Research Achievements

The dynamics and functional regulation of Treg in the intestine at the single cell level is unknown. It has been reported that the number of Treg in the mucosa is increased in patients with ulcerative colitis compared with that in healthy intestine. On the other hand, chronicity of intestinal inflammation and insufficient epithelial repair are shown in this patient. In order to analyze the dynamics of Treg in gastrointestinal diseases, this study used IVM to investigate the localization of Treg in the intestinal mucosa during inflammation in an in vivo model. In this study, we used IVM to examine the frequency and dynamics of intramucosal localization of Treg (between the mucosal lamina propria and intestinal epithelium) and mucosal lamina propria-epithelium cross-migration during inflammation in an in vivo model.

Academic Significance and Societal Importance of the Research Achievements

消化管内における１つの細胞がどこにいて、どのように動きを制御されているかについてはいままで不明であった。腸管の一つ一つの細胞がどこに存在しどのように動いているのかを可視化することに成功した。人の病気でも同様に可視化することが可能であり、局在、動態の違いから病気の原因解明につながる可能性がある。

Research Products

• [Journal Article] Various Endoscopic Features in Monomorphic Epitheliotropic Intestinal T-Cell Lymphoma (2021)
  • Author(s): Aoki Yasuhiro、Sujino Tomohisa、Takabayashi Kaoru、Mutakuchi Makoto、Emoto Katsura、Hosoe Naoki、Ogata Haruhiko、Kanai Takanori
  • Journal Title: Case Reports in Gastroenterology Volume: 1 Issue: 1 Pages: 312-322
  • DOI: 10.1159/000513902
  • Peer Reviewed / Open Access
• [Journal Article] Significance of endoscopic deep small bowel evaluation using balloon-assisted enteroscopy for Crohn's disease in clinical remission (2021)
  • Author(s): Takabayashi K, Hosoe N, Kato M, Hayashi Y, Nanki K, Fukuhara K, Mikami Y, Mizuno S, Sujino T, Mutaguchi M, Naganuma M, Yahagi N, Ogata H, Kanai T.
  • Journal Title: J Gastroenterol. Volume: 56(1) Issue: 1 Pages: 25-33
  • DOI: 10.1007/s12328-020-01261-x
  • Peer Reviewed
• [Journal Article] Characteristics of the Mucosal Surface on Scanning Electron Microscopy in Patients with Remitting Ulcerative Colitis (2021)
  • Author(s): Nomura E, Sujino T, Hosoe N, Yoshimatsu Y, Tanemoto S, Takabayashi K, Mutaguchi M, Shimoda M, Naganuma M, Ogata H, Kanai T.
  • Journal Title: Dig Dis Sci. Volume: - Issue: 9 Pages: 1-6
  • DOI: 10.1007/s10620-020-06609-4
  • Peer Reviewed / Open Access
• [Journal Article] Clinical, Endoscopic, and Pathological Characteristics of Immune Checkpoint Inhibitor-Induced Gastroenterocolitis (2021)
  • Author(s): Hayashi Y, Hosoe N, Takabayashi K, Limpias Kamiya KJL, Tsugaru K, Shimozaki K, Hirata K, Fukuhara K, Fukuhara S, Mutaguchi M, Sujino T, Sukawa Y, Hamamoto Y, Naganuma M, Takaishi H, Shimoda M, Ogata H, Kanai T.
  • Journal Title: Dig Dis Sci. Volume: - Issue: 6 Pages: 1-6
  • DOI: 10.1007/s10620-020-06441-w
  • Peer Reviewed
• [Journal Article] Clinical and Endoscopic Characteristics of Pyogenic Granuloma in the Small Intestine: A Case Series with Literature Review (2020)
  • Author(s): Hayashi Yukie、Hosoe Naoki、Takabayashi Kaoru、Kamiya Kenji JL Limpias、Mutaguchi Makoto、Miyanaga Ryoichi、Hirata Kenro、Fukuhara Seiichiro、Mikami Yohei、Sujino Tomohisa、Masugi Yohei、Naganuma Makoto、Ogata Haruhiko、Kanai Takanori
  • Journal Title: Internal Medicine Volume: 59 Issue: 4 Pages: 501-505
  • DOI: 10.2169/internalmedicine.3745-19
  • NAID: 130007798397
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2020-02-15
  • Peer Reviewed / Open Access
• [Journal Article] Significance of endoscopic deep small bowel evaluation using balloon-assisted enteroscopy for Crohn’s disease in clinical remission (2020)
  • Author(s): Takabayashi Kaoru、Hosoe Naoki、Kato Motohiko、Hayashi Yukie、Nanki Kosaku、Fukuhara Kayoko、Mikami Yohei、Mizuno Shinta、Sujino Tomohisa、Mutaguchi Makoto、Naganuma Makoto、Yahagi Naohisa、Ogata Haruhiko、Kanai Takanori
  • Journal Title: Journal of Gastroenterology Volume: 56 Issue: 1 Pages: 25-33
  • DOI: 10.1007/s00535-020-01737-0
  • Peer Reviewed / Open Access
• [Journal Article] The liver-brain-gut neural arc maintains the Treg cell niche in the gut (2020)
  • Author(s): Teratani T, Mikami Y, Nakamoto N, Suzuki T, Harada Y, Okabayashi K, Hagihara Y, Taniki N, Kohno K, Sibata S, Miyamoto K, Ishigame H, Chu Po-Sung, Sujino T, Suda W, Hattori M, Matsui M, Okada T, Okano H, Inoue M, Yada T, Kitagawa Y, Yoshimura A, Tanida M, Tsuda M, Iwasaki Y, Kanai T.
  • Journal Title: Nature Volume: 585 Issue: 7826 Pages: 591-596
  • DOI: 10.1038/s41586-020-2425-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Efficacy of Novel Ultrathin Single-Balloon Enteroscopy for Crohn's Disease: A Propensity Score-Matched Study (2019)
  • Author(s): Takabayashi Kaoru、Hosoe Naoki、Kato Motohiko、Hayashi Yukie、Miyanaga Ryoichi、Nanki Kosaku、Fukuhara Kayoko、Mikami Yohei、Mizuno Shinta、Sujino Tomohisa、Mutaguchi Makoto、Naganuma Makoto、Yahagi Naohisa、Ogata Haruhiko、Kanai Takanori
  • Journal Title: Gut and Liver Volume: - Issue: 5 Pages: 1-6
  • DOI: 10.5009/gnl19228
  • Peer Reviewed / Open Access
• [Journal Article] Plasmacytoid dendritic cells protect against immune-mediated acute liver injury via IL-35. (2019)
  • Author(s): Koda Y, Nakamoto N, Chu P, Ugamura A, Teratani T, Shiba S, Taniki N, Sujino T, Miyamoto K, Mikami Y, Suzuki T, Yamaguchi A, Morikawa R, Sato K, Yoshimoto T, Kanai K.
  • Journal Title: J Clin Invest Volume: 129(8) Issue: 8 Pages: 3201-3213
  • DOI: 10.1172/jci125863
  • Peer Reviewed / Open Access
• [Journal Article] Development of an Indigo Naturalis Suppository for Topical Induction Therapy in Patients with Ulcerative Colitis (2019)
  • Author(s): Yoshimatsu Yusuke、Naganuma Makoto、Sugimoto Shinya、Tanemoto Shun、Umeda Satoko、Fukuda Tomohiro、Nomura Ena、Yoshida Kosuke、Ono Keiko、Mutaguchi Makoto、Nanki Kosaku、Mizuno Shinta、Mikami Yohei、Fukuhara Kayoko、Sujino Tomohisa、Takabayashi Kaoru、Ogata Haruhiko、Iwao Yasushi、Kanai Takanori
  • Journal Title: Digestion Volume: 1 Issue: 4 Pages: 1-7
  • DOI: 10.1159/000501152
  • Peer Reviewed / Open Access