Analysis of liver NK cell activation mechanisms through CXCL9/CXCR3 chemokine axis

• Project/Area Number: 15K19893
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Hiroshima University
• Principal Investigator: Ohira Masahiro 広島大学, 病院(医), 病院助教 (30397947)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: NK細胞 / TRAIL / ケモカイン / 肝切除 / 肝癌

Outline of Final Research Achievements

Liver resident natural killer (NK) cells express tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a critical molecule for NK cell-mediated tumor cell killing.
TRAIL+ NK cells strongly and exclusively expressed CXCR3. CXCL9, a ligand of CXCR3, was significantly decreased in the liver after hepatectomy. The kinetics of hepatic CXCL9 expression resembled those of hepatic TRAIL+ NK cell proportions after hepatectomy. Among liver-resident mononuclear cells, macrophages predominantly secreted CXCL9 in response to interferon (IFN)-gamma stimulation. Although the administration of poly I:C, an inducer of IFN-gamma, increased hepatic CXCL9 levels in both CXCR3-/- and WT mice, even after hepatectomy, only WT mice recovered TRAIL expression on NK cells. Major hepatectomy remarkably reduced the proportion of TRAIL-expressing NK cells in the liver through downregulation of the CXCL9-CXCR3 axis in mice.

Research Products

• [Journal Article] CD52-Negative NK Cells Are Abundant in the Liver and Less Susceptible to Alemtuzumab Treatment. (2016)
  • Author(s): Hotta R, Ohira M, Matsuura T, Muraoka I, Tryphonopoulos P, Fan J, Tekin A, Selvaggi G, Levi D, Ruiz P, Ricordi C, Vianna R, Ohdan H, Waldmann H, Tzakis AG, and Nishida S.
  • Journal Title: PLoS One Volume: 11 Issue: 8 Pages: e0161618-e0161618
  • DOI: 10.1371/journal.pone.0161618
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Intraoperative assessment of tissue oxygen saturation of the remnant stomach by near-infrared spectroscopy in two cases of pancreatectomy following gastrectomy. (2016)
  • Author(s): Akabane S, Ohira M, Ishiyama K, Kobayashi T, Ide K, Tahara H, Kuroda S, Tanimine N, Shimizu S, Tanabe K, and Ohdan H.
  • Journal Title: International journal of surgery case reports Volume: 22 Pages: 75-78
  • DOI: 10.1016/j.ijscr.2016.03.047
  • Peer Reviewed / Open Access
• [Journal Article] Intrahepatic cholangiocarcinoma coinciding with a liver metastasis from a rectal carcinoma: a case report. (2016)
  • Author(s): Akabane S, Ohira M, Kobayashi T, Kuroda S, Tanimine N, Shimizu S, Tahara H, Ide K, Ishiyama K, Egi H, Tanabe K, Sentani K, Yasui W, and Ohdan H.
  • Journal Title: Surg Case Rep Volume: 2 Issue: 1 Pages: 94-94
  • DOI: 10.1186/s40792-016-0222-x
  • Peer Reviewed / Open Access
• [Journal Article] Elective laparoscopic deroofing to treat the spontaneous rupture of a large simple liver cyst: a case report. (2016)
  • Author(s): Imaoka Y, Ohira M, Kobayashi T, Shimizu S, Tahara H, Kuroda S, Ide K, Ishiyama K, and Ohdan H.
  • Journal Title: Surg Case Rep Volume: 2 Issue: 1 Pages: 148-148
  • DOI: 10.1186/s40792-016-0275-x
  • Peer Reviewed / Open Access
• [Presentation] ドナー肝臓由来活性化ナチュラルキラー細胞移入療法による肝臓移植後重症感染症予防（第I/II相試験） (2017)
  • Author(s): 大平真裕 矢野琢也 中野亮介 田中友加 大段秀樹
  • Organizer: 第16回日本再生医療学会総会
  • Place of Presentation: 仙台
  • Year and Date: 2017-03-07
• [Presentation] Corticosteroids dampen Natural Killer cell function including cytotoxicity and anti-HCV effect (2016)
  • Author(s): Masahiro Ohira Ryuichi Hotta, Takuya Yano, Ryosuke Nakano, Andreas Tzakis, Seigo Nishida, Hideki Ohdan
  • Organizer: Asian Transplantation Week 2016
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2016-10-27
  • Int'l Joint Research
• [Presentation] 肝移植後肝癌再発におけるNK細胞機能脆弱化のメカニズムの解明 (2016)
  • Author(s): 矢野琢也 大平真裕, 中野亮介, 石山宏平, 井手健太郎, 田原裕之, 清水誠一, 佐伯吉弘, 坂井寛, 石田伸樹, 柳川泉一郎, 田中飛鳥, 尾上隆司, 田中友加, 大段秀樹.
  • Organizer: 第52回日本移植学会総会
  • Place of Presentation: 東京
  • Year and Date: 2016-09-29
• [Presentation] Reduction in CXCL9-CXCR3 signals diminishes TRAIL-expressing liver NK cells in partially hepatectomized mice under depressed immune status. (2016)
  • Author(s): Yano T Ohira M, Nakano R, Ohdan H.
  • Organizer: 26th International Congress of the Transplantation Society
  • Place of Presentation: Hong Kong, China
  • Year and Date: 2016-08-18
  • Int'l Joint Research
• [Presentation] Immunotherapy using donor liver NK cells for preventing severe infection after liver transplantation (2016)
  • Author(s): 大平真裕 石山宏平, 小林剛, 井手健太郎, 田原裕之, 矢野琢也, 清水誠一, 中野亮介, 大段秀樹.
  • Organizer: 第71回日本消化器外科学会総会
  • Place of Presentation: 徳島
  • Year and Date: 2016-07-13
• [Presentation] 肝切除後肝臓癌再発における肝臓内NK細胞機能低下メカニズムの解明 (2016)
  • Author(s): 矢野琢也 大平真裕, 中野亮介, 石山宏平, 井手健太郎, 田原裕之, 佐伯吉弘, 石田伸樹, 田中友加, 大段秀樹.
  • Organizer: 第71回日本消化器外科学会総会
  • Place of Presentation: 徳島
  • Year and Date: 2016-07-13
• [Presentation] ドナー肝臓由来活性化ナチュラルキラー 細胞移入療法による肝臓移植後 重症感染症予防（第I/II相試験） (2016)
  • Author(s): 大平真裕 清水誠一, 矢野琢也, 中野亮介, 堀田龍一, 田原裕之, 井手健太郎, 小林剛, 石山宏平, 田中友加, 大段秀樹
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: 千葉
  • Year and Date: 2016-05-19
• [Presentation] 肝癌再発予防のための肝切除後ケモカイン低下による肝臓内NK 細胞機能低下の解析 (2016)
  • Author(s): 矢野琢也 大平真裕, 中野亮介, 石山宏平, 井手健太郎, 田原裕之, 谷峰直樹, 佐伯吉弘, 清水誠一, 坂井寛, 広瀬貴行, 柳川泉一郎, 田中飛鳥, 田口和浩, 田中友加, 田代裕尊, 大段秀樹.
  • Organizer: 第116回日本外科学会定期学術集会
  • Place of Presentation: 大阪
  • Year and Date: 2016-04-14
• [Presentation] 肝臓切除後におけるNK細胞機能の脆弱化のメカニズム (2016)
  • Author(s): 矢野琢也 大平真裕, 中野亮介, 大段秀樹.
  • Organizer: 第12回広島肝臓プロジェクト研究センター シンポジウム
  • Place of Presentation: 広島
• [Presentation] 肝切除による肝臓内免疫機能低下におけるメカニズムの解明と制御 (2015)
  • Author(s): 矢野琢也、大平真裕、大段秀樹
  • Organizer: 第51回日本移植学会総会
  • Place of Presentation: ホテル日航熊本、熊本県熊本市
  • Year and Date: 2015-10-02
• [Presentation] Significant reduction in TRAIL-expressing NK cells in remnant liver after partial hepatectomy is strongly associated with the impaired intrahepatic CXCL9–CXCR3 pathway (2015)
  • Author(s): Takuya Yano, Masahiro Ohira, Hideki Ohdan
  • Organizer: 2015American Transplant Congress
  • Place of Presentation: Philadelphia, USA
  • Year and Date: 2015-05-05
  • Int'l Joint Research
• [Presentation] 肝切除による肝臓内免疫機能低下メカニズムの解明と制御 (2015)
  • Author(s): 矢野琢也、大平真裕、大段秀樹
  • Organizer: 第115回日本外科学会定期学術集会
  • Place of Presentation: 名古屋国際会議場、愛知県名古屋市
  • Year and Date: 2015-04-16