Clarification of the pathogenecity and the application of therapies from biliary epithelial cells in primary biliary cholangitis

• Project/Area Number: 26461012
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyushu University
• Principal Investigator: Shimoda Shinji 九州大学, 大学病院, 准教授 (30279319)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 原発性胆汁性胆管炎 / anion exchanger 2 / 疎水性胆汁酸 / IFN-g / 細胞老化 / 悪性サイクル / PBC / NLRP3 / IL-1b / 胆管細胞 / NK細胞 / 原発性胆汁性肝硬変 / インフラマソーム

Outline of Final Research Achievements

To address the role of AE2 in preventing PBC pathogenesis, we took advantage of our ability to isolate human BEC and autologous splenic mononuclear cells (SMC). We studied the influence of hydrophobic bile acids (GCDC), on AE2 expression in BEC and the subsequent impact on the phenotypes of BEC and local inflammatory responses. We demonstrate herein that GCDC reduces AE2 expression in BEC through induction of ROS, which enhances senescence of BEC. In addition, a reduction of AE2 levels upregulates the production of IL-6, IL-8 and CXCL10 from BEC in response to toll like receptor ligands.

Research Products

• [Journal Article] Hydrophobic bile acids suppress expression of AE2 in biliary epithelial cells and induce bile duct inflammation in primary biliary cholangitis (2016)
  • Author(s): Hisamoto S, Shimoda S, Harada K, et al
  • Journal Title: J Autoimmun Volume: 75 Pages: 150-160
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Natural killer cells regulate T cell immune responses in primary biliary cirrhosis. (2015)
  • Author(s): Shimoda S, Hisamoto S, Harada K, Iwasaka S, Chong Y, Nakamura M, Bekki Y, Yoshizumi T, Shirabe K, Ikegami T, Maehara Y, He XS, Gershwin ME, Akashi K.
  • Journal Title: Hepatology Volume: 62 Pages: 1817-1827
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Risk factors for hepatitis B virus recurrence after living donor liver transplantation: A 17-year experience at a single center. (2015)
  • Author(s): Bae SK, Shimoda S, Ikegami T, Yoshizumi T, Harimoto N, Itoh S, Soejima Y, Uchiyama H, Shirabe K, Maehara Y.
  • Journal Title: Hepatol Res. Volume: 45 Pages: 1203-1210
  • Peer Reviewed / Open Access
• [Journal Article] Comparative safety study on severe anemia by simeprevir- versus telaprevir-based triple therapy for chronic hepatitis C. (2015)
  • Author(s): Ogawa E, Furusyo N, Kajiwara E, Nomura H, Kawano A, Takahashi K, Dohmen K, Satoh T, Azuma K, Nakamuta M, Koyanagi T, Kotoh K, Shimoda S, Hayashi J
  • Journal Title: J Gastroenterol Hepatol. Volume: 30 Pages: 1309-1316
  • Peer Reviewed / Open Access
• [Journal Article] Bacterial Infection as an Adverse Effect of Telaprevir-based Triple Therapy for Chronic Hepatitis C Infection. (2015)
  • Author(s): Kawano A, Ogawa E, Furusyo N, Nakamuta M, Kajiwara E, Dohmen K, Nomura H, Takahashi K, Satoh T, Azuma K, Tanabe Y, Shimoda S, Kotoh K, Hayashi J; Kyushu University Liver Disease Study (KULDS) Group.
  • Journal Title: Intern Med. Volume: 54 Pages: 567-572
  • NAID: 130004903089
  • Peer Reviewed / Open Access
• [Journal Article] Effectiveness of triple therapy with simeprevir for chronic hepatitis C genotype 1b patients with prior telaprevir failure. (2015)
  • Author(s): Ogawa E, Furusyo N, Dohmen K, Kajiwara E, Kawano A, Nomura H, Takahashi K, Satoh T, Azuma K, Nakamuta M, Koyanagi T, Kotoh K, Shimoda S, Hayashi J; Kyushu University Liver Disease Study (KULDS) Group.
  • Journal Title: J Viral Hepat. Volume: 22 Pages: 992-1001
  • Peer Reviewed / Open Access
• [Journal Article] Comparative effectiveness and safety study of triple therapy with simeprevir or telaprevir for non-cirrhotic patients with chronic hepatitis C virus genotype 1b infection. (2015)
  • Author(s): Ogawa E, Furusyo N, Kajiwara E, Nomura H, Kawano A, Takahashi K, Dohmen K, Satoh T, Azuma K, Nakamuta M, Koyanagi T, Kotoh K, Shimoda S, Hayashi J.
  • Journal Title: J Gastroenterol Hepatol. Volume: 30 Pages: 1759-1767
  • Peer Reviewed / Open Access
• [Journal Article] Decreased secretion of Paneth cell α-defensins in graft-versus-host disease. (2015)
  • Author(s): Eriguchi Y, Nakamura K, Hashimoto D, Shimoda S, Shimono N, Akashi K, Ayabe T, Teshima T.
  • Journal Title: Transpl Infect Dis. Volume: 17 Pages: 702-706
  • Peer Reviewed / Open Access
• [Journal Article] Risk Factors Associated with Stenotrophomonas maltophilia Bacteremia: A Matched Case-Control Study. (2015)
  • Author(s): Sumida K, Chong Y, Miyake N, Akahoshi T, Yasuda M, Shimono N, Shimoda S, Maehara Y, Akashi K.
  • Journal Title: PLoS One. Volume: 24 Pages: 1-8
  • Peer Reviewed / Open Access
• [Journal Article] A dramatic increase in the positive blood culture rates of Helicobacter cinaedi: the evidence of differential detection abilities between the Bactec and BacT/Alert systems. (2015)
  • Author(s): Miyake N, Chong Y, Nishida R, Nagasaki Y, Kibe Y, Kiyosuke M, Shimomura T, Shimono N, Shimoda S, Akashi K.
  • Journal Title: Diagn Microbiol Infect Dis. Volume: 83 Pages: 232-233
  • Peer Reviewed / Open Access
• [Journal Article] Importance of virological response in the early stage of telaprevir-based triple therapy for hepatitis C. (2015)
  • Author(s): Hiramine S, Furusyo N, Ogawa E, Nakamuta M, Kajiwara E, Nomura H, Dohmen K, Takahashi K, Satoh T, Azuma K, Kawano A, Koyanagi T, Kotoh K, Shimoda S, Hayashi J.
  • Journal Title: World J Hepatol. Volume: 18 Pages: 2688-2695
  • Peer Reviewed / Open Access
• [Journal Article] Alteration of energy metabolism in the pathogenesis of bile duct lesions in primary biliary cirrhosis. (2014)
  • Author(s): Harada K, Kakuda Y, Sato Y, Ikeda H, Shimoda S, Yamamoto Y, Inoue H, Ohta H, Kasashima S, Kawashima A, Nakanuma Y.
  • Journal Title: J Clin Pathol Volume: 67(5) Issue: 5 Pages: 396-402
  • DOI: 10.1136/jclinpath-2013-201815
  • NAID: 120005469783
  • Peer Reviewed / Open Access
• [Journal Article] Systemic and local expression levels of TNF-like ligand 1A and its decoy receptor 3 are increased in primary biliary cirrhosis. (2013)
  • Author(s): Aiba Y, Harada K, Komori A, Ito M, Shimoda S, Nakamura H, Nagaoka S, Abiru S, Migita K, Ishibashi H, Nakanuma Y, Nishida N, Kawashima M, Tokunaga K, Yatsuhashi H, Nakamura M.
  • Journal Title: Liver Int. Volume: 34 Issue: 5 Pages: 679-688
  • DOI: 10.1111/liv.12296
  • Peer Reviewed
• [Presentation] PBC胆管炎を模倣したAE2発現低下による胆管細胞での慢性炎症の誘導 (2016)
  • Author(s): 下田慎治
  • Organizer: 日本肝臓学会総会
  • Place of Presentation: 千葉市
  • Year and Date: 2016-05-19
• [Presentation] PBCでの胆管細胞AE2発現低下は慢性炎症性変化を亢進させる (2016)
  • Author(s): 下田慎治
  • Organizer: 日本消化器病学会総会
  • Place of Presentation: 新宿区
  • Year and Date: 2016-04-21
• [Presentation] 原発性胆汁性肝硬変におけるNK細胞による胆管細胞傷害機序の解析 (2015)
  • Author(s): 下田慎治
  • Organizer: 第４１回日本肝臓学会西部会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-12-03
• [Presentation] Natural killer cells regulate T cell immunity in primary biliary cirrhosis (2015)
  • Author(s): Shinji Shimoda
  • Organizer: アメリカ肝臓学会(AASLD)
  • Place of Presentation: San Francisco
  • Year and Date: 2015-11-13
  • Int'l Joint Research
• [Presentation] 胆管細胞から明らかにするPBCの病態 (2015)
  • Author(s): 下田慎治
  • Organizer: 第５７回日本消化器病学会大会
  • Place of Presentation: 東京
  • Year and Date: 2015-10-08
• [Presentation] 原発性胆汁性肝硬変をモデルにした臓器特異的自己免疫疾患における自然免疫異常から獲得免疫異常へ移行するメカニズムの解析 (2015)
  • Author(s): 下田慎治
  • Organizer: 第５１回日本肝臓学会総会
  • Place of Presentation: 熊本市
  • Year and Date: 2015-05-21
• [Presentation] HCV陽性肝硬変におけるT細胞機能に関する脾臓の役割 (2015)
  • Author(s): 下田慎治
  • Organizer: 第１０１回日本消化器病学会総会
  • Place of Presentation: 仙台市
  • Year and Date: 2015-04-23
• [Presentation] 原発性胆汁性肝硬変の病態形成における疎水性胆汁酸とanion exchager2の関与 (2014)
  • Author(s): 久本 仁美, 岩坂 翔, 隅田 幸佑, 原田 憲一, 下田 慎治
  • Organizer: 日本肝臓学会
  • Place of Presentation: 東京
  • Year and Date: 2014-05-29 – 2014-05-30