Underlying mechanism of liver repair mediated by iNKT cells

• Project/Area Number: 20K17630
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kitasato University
• Principal Investigator: NISHIZAWA NOBUYUKI 北里大学, 医学部, 助教 (60566925)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 肝 / 虚血再灌流障害 / NKT細胞 / マクロファージ / 肝修復 / 肝臓 / 組織修復 / 免疫細胞 / ＮＫＴ細胞 / 炎症

Outline of Research at the Start

肝臓に豊富に分布する免疫細胞Natural Killer T cell (NKT)細胞は樹状細胞から抗原提示を受けてリンパ球に獲得免疫作用を発揮させるが、組織修復にも関与する可能性が最近報告された。しかしながら虚血再潅流障害後の肝修復における肝NKT細胞の役割は不明である。本研究では肝修復にはPGE2を介した肝NKT細胞と肝樹状細胞とのクロストークが重要な役割を果たしていることと、その分子制御機構を解明することを目的とする。成果を踏まえ、肝NKT細胞を標的とした治療的意義を検討し、新たな肝再生治療の臨床的応用を目指す。

Outline of Final Research Achievements

The role of NKT cells in liver tissue repair after hepatic ischemia-reperfusion injury was investigated. α-galactosylcerimide-treated activated NKT cells interacted with macrophages and produced IL-4 and IFN-γ, which accelerated the differentiation of macrophages accumulating in the liver and promoted liver repair. This interaction was demonstrated to be crucial for cytokine synthesis in the NKT cell-macrophage co-culture system. Activated NKT cells have the potential to enhance liver tissue repair after acute liver injury.

Academic Significance and Societal Importance of the Research Achievements

肝虚血再灌流後の肝組織修復が障害されると肝不全に至り患者予後は不良となる。これまでマクロファージの形質転換が肝修復に必須であるがその機序は不明であった。本研究において、NKT細胞とマクロファージの相互作用がマクロファージ形質転換に寄与して肝修復を促進することが明らかになった。NKT細胞を標的とした新しい肝再生治療開発に結びつく可能性が期待される。

Research Products

• [Journal Article] Expansion of iNKT Cells Promotes Liver Repair Following Hepatic Ischemia Reperfusion Injury (2022)
  • Author(s): GOTO TAKUYA、ITO YOSHIYA、NISHIZAWA NOBUYUKI、KURODA YU、NAKAMOTO SHUJI、HOSONO KANAKO、NAITOH TAKESHI、HIKI NAOKI、AMANO HIDEKI
  • Journal Title: In Vivo Volume: 36 Issue: 6 Pages: 2604-2614
  • DOI: 10.21873/invivo.12995
  • Peer Reviewed / Open Access
• [Journal Article] A case of solid-type pancreatic hamartoma presenting high apparent diffusion coefficient value: histopathological correlation and literature review (2022)
  • Author(s): Woo J, Haradome H, Adachi K, Iwai T, Nishizawa N, Murakumo Y, Kusano C, Kumamoto Y, Inoue Y, Ojiri H
  • Journal Title: Abdom Radiol Volume: - Issue: 6 Pages: 1939-1947
  • DOI: 10.1007/s00261-022-03442-3
  • Peer Reviewed
• [Journal Article] Pancreas-contactless gastrectomy for gastric cancer prevents postoperative inflammation. (2022)
  • Author(s): Ushiku H, Sakuraya M, Washio M, Hosoda K, Niihara M, Harada H, Miura H, Sato T, Nishizawa N, Tajima H, Kaizu T, Kato H, Sengoku N, Tanaka K, Naitoh T, Kumamoto Y, Sangai T, Yamashita K, Hiki N.
  • Journal Title: Surg Endosc. Volume: - Issue: 8 Pages: 5644-5651
  • DOI: 10.1007/s00464-021-08961-6
  • Peer Reviewed
• [Journal Article] Activation of iNKT Cells Facilitates Liver Repair After Hepatic Ischemia Reperfusion Injury Through Acceleration of Macrophage Polarization. (2021)
  • Author(s): Goto T, Ito Y, Satoh M, Nakamoto S, Nishizawa N, Hosono K, Naitoh T, Eshima K, Iwabuchi K, Hiki N, Amano H.
  • Journal Title: Front Immunol. Volume: 12 Pages: 754106-754106
  • DOI: 10.3389/fimmu.2021.754106
  • Peer Reviewed / Open Access
• [Journal Article] Macrophages contribute to liver repair after monocrotaline-induced liver injury via SDF-1/CXCR4. (2021)
  • Author(s): Otaka F, Ito Y, Nakamoto S, Nishizawa N, Hyodo T, Hosono K, Majima M, Koizumi W, Amano H.
  • Journal Title: Exp Ther Med Volume: 22 Issue: 1 Pages: 668-668
  • DOI: 10.3892/etm.2021.10100
  • Peer Reviewed / Open Access
• [Journal Article] Prospective study to validate the clinical utility of DNA diagnosis of peritoneal fluid cytology test in gastric cancer (2021)
  • Author(s): Harada Hiroki、Soeno Takafumi、Nishizawa Nobuyuki、Washio Marie、Sakuraya Mikiko、Ushiku Hideki、Niihara Masahiro、Hosoda Kei、Kumamoto Yusuke、Naitoh Takeshi、Sangai Takafumi、Hiki Naoki、Yamashita Keishi
  • Journal Title: Cancer Science Volume: 112 Issue: 4 Pages: 1644-1654
  • DOI: 10.1111/cas.14850
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Lymphangiogenesis and accumulation of reparative macrophages contribute to liver repair after hepatic ischemia?reperfusion injury (2020)
  • Author(s): Nakamoto Shuji、Ito Yoshiya、Nishizawa Nobuyuki、Goto Takuya、Kojo Ken、Kumamoto Yusuke、Watanabe Masahiko、Majima Masataka
  • Journal Title: Angiogenesis Volume: 23 Issue: 3 Pages: 395-410
  • DOI: 10.1007/s10456-020-09718-w
  • Peer Reviewed / Open Access
• [Journal Article] EP3 signaling in dendritic cells promotes liver repair by inducing IL-13-mediated macrophage differentiation in mice. (2020)
  • Author(s): Nakamoto S, Ito Y, Nishizawa N, Goto T, Kojo K, Kumamoto Y, Watanabe M, Narumiya S, Majima M.
  • Journal Title: FASEB J Volume: 34 Issue: 4 Pages: 5610-5627
  • DOI: 10.1096/fj.201901955r
  • Peer Reviewed / Open Access
• [Journal Article] Promoter DNA Hypermethylation of the Cysteine Dioxygenase 1 (CDO1) Gene in Intraductal Papillary Mucinous Neoplasm (IPMN) (2020)
  • Author(s): Fujiyama Yoshiki、Kumamoto Yusuke、Nishizawa Nobuyuki、Nakamoto Shuji、Harada Hiroki、Yokota Kazuko、Tanaka Yoko、Igarashi Kazuharu、Oiki Hironobu、Okuwaki Kosuke、Iwai Tomohisa、Kajita Sabine、Takahashi Hiroyuki、Tajima Hiroshi、Kaizu Takashi、Sasaki Jiichiro、Watanabe Masahiko、Yamashita Keishi
  • Journal Title: Annals of Surgical Oncology Volume: 27 Issue: 10 Pages: 4007-4016
  • DOI: 10.1245/s10434-020-08291-2
  • Peer Reviewed / Open Access
• [Journal Article] Prediction of Efficacy of Postoperative Chemotherapy by DNA Methylation of CDO1 in Gastric Cancer (2020)
  • Author(s): Harada Hiroki、Soeno Takafumi、Yokoi Keigo、Nishizawa Nobuyuki、Ushiku Hideki、Hosoda Kei、Hiki Naoki、Yamashita Keishi
  • Journal Title: Journal of Surgical Research Volume: 256 Pages: 404-412
  • DOI: 10.1016/j.jss.2020.07.001
  • Peer Reviewed / Open Access
• [Presentation] 膵癌に対する腹腔鏡下尾側膵切除術の手術手技と短期成績 (2021)
  • Author(s): 西澤 伸恭, 田島 弘, 贄 裕亮, 岡本 光祈子, 久保 任史, 三浦 啓壽, 加藤 弘, 海津 貴史,仙石 紀彦, 細田 桂, 比企 直樹, 佐藤 武郎, 三階 貴史, 内藤 剛, 田中 潔, 隈元 雄介
  • Organizer: 第121回日本外科学会定期学術集会
• [Presentation] 樹状細胞のEP3シグナル伝達はマウスの虚血再灌流障害後の肝修復を促進する (2020)
  • Author(s): 中本 修司、伊藤 義也、後藤 卓也、西澤 伸恭、古城 憲、隈元 雄介、馬嶋 正隆
  • Organizer: 第93回日本薬理学会年会
• [Presentation] CDO1遺伝子DNAメチル化による膵癌新規診断法の有用性の検討 (2020)
  • Author(s): 西澤 伸恭, 山下 継史, 藤山 芳樹, 中本 修司, 久保 任史, 田島 弘, 海津 貴史, 隈元 雄介
  • Organizer: 日本外科学会定期学術集会
• [Presentation] 腹腔鏡下肝切除における亜区域以上肝切除の安全性 単施設450例の検討 (2020)
  • Author(s): 海津 貴史, 田島 弘, 西澤 伸恭, 久保 任史, 隈元 雄介
  • Organizer: 日本外科学会定期学術集会
• [Presentation] 大腸癌肝転移症例に対する腹腔鏡下手術の安全性 117例の検討 (2020)
  • Author(s): 藤山 芳樹, 海津 貴史, 永 滋教, 中本 修司, 西澤 伸恭, 久保 任史, 田島 弘, 隈元 雄介
  • Organizer: 日本外科学会定期学術集会