Control of liver fibrosis after transplantation by immunomodulation

• Project/Area Number: 23390322
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Digestive surgery
• Research Institution: Kyoto University
• Principal Investigator: KOJIRO Taura 京都大学, 医学(系)研究科(研究院), 助教 (80378629)
• Co-Investigator(Kenkyū-buntansha): UEMOTO Shinji 京都大学, 医学研究科, 教授 (40252449) ; HATANO Etsuro 京都大学, 医学研究科, 講師 (80359801)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥19,110,000 (Direct Cost: ¥14,700,000、Indirect Cost: ¥4,410,000); Fiscal Year 2013: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2012: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000); Fiscal Year 2011: ¥9,360,000 (Direct Cost: ¥7,200,000、Indirect Cost: ¥2,160,000)
• Keywords: 肝線維化 / 肝移植 / 脾臓 / 免疫 / 肝線進化 / 星細胞 / Helper T細胞 / サイトカイン

Research Abstract

To investigate the effects of splenectomy on liver fibrosis, BALB/c mice underwent splenectomy or sham operation and subjected to carbon tetrachloride (CCl4) or thioacetamide (TAA) treatments. Splenectomy significantly suppressed liver fibrosis in the CCl4 and TAA models. The inhibitory effect of splenectomy on liver fibrosis was not observed in SCID mice.
To investigate the mechanisms underlying these effects, we investigated the change of liver Th1/Th2 balance. As a result, splenectomy shifted Th1/Th2 balance toward Th1-dominance. In addition, the number of CD4+ lymphocytes in the spleen was decreased. In contrast, that in the liver was increased. GFP+ splenic lymphocytes were transplanted into the spleen of wild type mice. GFP+CD4+ lymphocytes appeared in the liver after induction of fibrosis and the vast majority of them were Th2 lymphocytes by flow cytometry.
We conclude that splenectomy suppresses progression of liver fibrosis at least partly through restoring the Th1/Th2 balance.

Research Products

• [Journal Article] The impact of posthepatectomy liver failure on the recurrence of hepatocellular carcinoma (2014)
  • Author(s): Iguchi K, Hatano E, Yamanaka K, Tanaka S, Taura K, Uemoto S
  • Journal Title: World J Surg Volume: 38(1) Issue: 1 Pages: 150-158
  • DOI: 10.1007/s00268-013-2247-7
  • Peer Reviewed
• [Journal Article] Direct volume manipulation for visualizing intraoperative liver resection process (2014)
  • Author(s): Nakao M, Oda Y, Taura K, Minato K
  • Journal Title: Comput Methods Programs Biomed Volume: 113(3) Issue: 3 Pages: 725-735
  • DOI: 10.1016/j.cmpb.2013.12.004
  • NAID: 120005399110
  • Peer Reviewed
• [Journal Article] Effect of olprinone on liver microstructure in rat partial liver transplantation (2013)
  • Author(s): Yamanaka K, Hatano E, Iguchi K, Yamamoto G, Sato M, Toriguchi K, Tanabe K, Takemoto K, Nakamura K, Koyama N, Narita M, Nagata H, Taura K, Uemoto S
  • Journal Title: J Surg Res Volume: 183(1) Issue: 1 Pages: 391-396
  • DOI: 10.1016/j.jss.2012.11.033
  • NAID: 120005298136
  • Peer Reviewed
• [Journal Article] Effects of oral intake of hydrogen water on liver fibrogenesis in mice (2013)
  • Author(s): Koyama Y, Taura K, Hatano E, Tanabe K, Yamamoto G, Nakamura K, Yamanaka K, Kitamura K, Narita M, Nagata H, Yanagida A, Iida T, Iwaisako K, Fujinawa H, Uemoto S
  • Journal Title: Hepatol Res Volume: May 20 Issue: 6 Pages: 663-677
  • DOI: 10.1111/hepr.12165
  • Peer Reviewed
• [Journal Article] Soluble thrombomodulin attenuates sinusoidal obstruction syndrome in rat through suppression of high mobility group box 1 (2013)
  • Author(s): Nakamura K, Hatano E, Miyagawa-Hayashino A, Okuno M, Koyama Y, Narita M, Seo S, Taura K, Uemoto S
  • Journal Title: Liver Int Volume: Nov 29 Issue: 10 Pages: 1473-1487
  • DOI: 10.1111/liv.12420
  • Peer Reviewed
• [Journal Article] Origin of myofibroblasts in liver fibrosis. (2012)
  • Author(s): Brenner DA
  • Journal Title: Fibrogenesis Tissue Repair. Volume: Jun 6;5 Suppl 1 Issue: S1
  • DOI: 10.1186/1755-1536-5-s1-s17
  • Peer Reviewed
• [Journal Article] Sorafenib attenuates monocrotaline-induced sinusoidal obstruction syndrome in rats through suppression of JNK and MMP-9. (2012)
  • Author(s): Nakamura Koijro
  • Journal Title: J Hepatol. Volume: Nov;57(5) Issue: 5 Pages: 1037-43
  • DOI: 10.1016/j.jhep.2012.07.004
  • Peer Reviewed
• [Journal Article] Protection from liver fibrosis by a peroxisome proliferator-activated receptor δ agonist (2012)
  • Author(s): Iwaisako K, Haimerl M, Paik YH, Taura K, Kodama Y, Sirlin C, Yu E, Yu RT, Downes M, Evans RM, Brenner DA, Schnabl B
  • Journal Title: Proc Natl Acad Sci U S A Volume: 109 Issue: 21 Pages: 1369-76
  • DOI: 10.1073/pnas.1202464109
  • Peer Reviewed
• [Journal Article] Non-alcoholic steatohepatitis-induced fibrosis : Toll-like receptors, reactive oxygen species and Jun N-terminal kinase (2011)
  • Author(s): Brenner DA, Seki E, Taura K, Kisseleva T, Deminicis S, Iwaisako K, Inokuchi S, Schnabl B, Oesterreicher CH, Paik YH, Miura K, Kodama Y
  • Journal Title: Hepatology Research Volume: 41 Issue: 7 Pages: 683-686
  • DOI: 10.1111/j.1872-034x.2011.00814.x
  • Peer Reviewed
• [Journal Article] Downregulation of the Wnt antagonist Dkk2 links the loss of Sept4 and myofibroblastic transformation of hepatic stellate cells (2011)
  • Author(s): Yanagida A, Iwaisako K, Hatano E, Taura K, Sato F, Narita M, Nagata H, Asechi H, Uemoto S, Kinoshita M
  • Journal Title: BBA-Molecular Basis of Disease Volume: 812 Issue: 11 Pages: 1403-1411
  • DOI: 10.1016/j.bbadis.2011.06.015
  • NAID: 120003517932
  • Peer Reviewed
• [Journal Article] Proliferative activity in hepatocellular carcinoma is closely correlated with glucose metabolism but not angiogenesis (2011)
  • Author(s): Kitamura K, Taura K, et al
  • Journal Title: J Hepatol Volume: 4 Pages: 846-857
  • Peer Reviewed
• [Presentation] Migration of splenic lymphocytes promotes fibrotic response in the liver through modification of T helper cytokine balance in mice (2014)
  • Author(s): K. Tanabe, K. Taura, Y. Koyama, G. Yamamoto, T. Nishio, E. Hatano, S. Uemoto
  • Organizer: Academic Surgical Congress
  • Place of Presentation: Manchester Grand Hyatt (San Diego, CA)
• [Presentation] Liver Stiffness Measurement Predicts Posthepatectomy Liver Failure (2014)
  • Author(s): K. Taura, Y. Koyama, K. Tanabe, G. Yamamoto, T. Nishio, E. Hatano, S. Uemoto
  • Organizer: Academic Surgical Congress
  • Place of Presentation: Manchester Grand Hyatt (San Diego, CA)
• [Presentation] 脾臓摘出術は肝臓におけるTh1/Th2 サイトカインバランスの変化を介して肝線維化を抑制する (2014)
  • Author(s): 田邉和孝, 田浦康二朗, 波多野悦朗, 小山幸法, 山本玄, 西尾太宏, 奥田雄紀浩, 中村公治郎, 鳥口寛, 竹本研史, 上本伸二
  • Organizer: 第114回日本外科学会定期学術集会
  • Place of Presentation: 国立京都国際会館(京都市)
• [Presentation] 肝静脈根部大型肝癌に対する肝切除術式 (2014)
  • Author(s): 田浦康二朗, 波多野悦朗, 安近健太郎, 瀬尾智, 福光剣, 上本伸二
  • Organizer: 第114回日本外科学会定期学術集会
  • Place of Presentation: 国立京都国際会館(京都市)
• [Presentation] 脾臓摘出術は肝臓におけるTh1/Th2サイトカインバランスの変化を介して肝線維化を抑制する (2014)
  • Author(s): 田邉和孝
  • Organizer: 日本外科学会
  • Place of Presentation: 国立京都国際会館（京都市）
• [Presentation] Liver Stiffness Measurement Predicts Posthepatectomy Liver Failure (PHLF) (2014)
  • Author(s): 田浦康二朗
  • Organizer: Academic Surgical Congress
  • Place of Presentation: Manchester Grand Hyatt (San Diego, CA)
• [Presentation] 肝静脈根部大型肝癌に対する肝切除術式 (2014)
  • Author(s): 田浦康二朗
  • Organizer: 日本外科学会
  • Place of Presentation: 国立京都国際会館（京都市）
• [Presentation] Three-Dimensional Image of Hepatic Hilum by CT Cholangiography with Carbon Dioxide for Preoperative Assessment of Biliary Malignancies (2012)
  • Author(s): 田浦康二朗
  • Organizer: Internationa Forum of Liver Surgery
  • Place of Presentation: セイコーグランドホテル(秋田県)
  • Year and Date: 2012-03-25
• [Presentation] 3D CT cholangiographyを活用した肝門部胆管癌に対する術式選択と手術プラニング (2012)
  • Author(s): 田浦 康二朗
  • Organizer: 日本外科学会総会
  • Place of Presentation: 幕張メッセ（千葉市）
• [Presentation] Plissimo Eraを用いた 肝切除術のVirtual Reality (2012)
  • Author(s): 田浦 康二朗
  • Organizer: 日本消化器外科学会
  • Place of Presentation: 富山国際会議場（富山市）
• [Presentation] Usefulness of Liver Stiffness Measurement for the Prediction of Posthepatectomy Liver Failure (2012)
  • Author(s): Taura Kojiro
  • Organizer: The 63rd Annual Meeting of the American Association for the Study of Liver Disease
  • Place of Presentation: Hynes Convention Center (Boston, USA)
• [Presentation] 肝胆膵外科における Virtual 3D画像と 臓器立体モデルへの取り組み (2012)
  • Author(s): 田浦 康二朗
  • Organizer: 日本内視鏡外科学会総会
  • Place of Presentation: パシフィコ横浜（横浜市）