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Analysis of IL-6-mediated drug-resistance of hepatitis C virus infection

Research Project

Project/Area Number 24590958
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionTokyo Medical and Dental University

Principal Investigator

NAKAGAWA Mina  東京医科歯科大学, 医歯学融合教育支援センター, 准教授 (30401342)

Co-Investigator(Kenkyū-buntansha) ASAHINA Yasuhiro  東京医科歯科大学, 大学院医歯学総合研究科, 寄附講座教授 (00422692)
WATANABE Mamoru  東京医科歯科大学, 大学院医歯学総合研究科, 教授 (10175127)
Co-Investigator(Renkei-kenkyūsha) SAKAMOTO Naoya  北海道大学, 医学研究科, 教授 (10334418)
Project Period (FY) 2012-04-01 – 2015-03-31
Project Status Completed (Fiscal Year 2014)
Budget Amount *help
¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000)
Fiscal Year 2014: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
Keywords治療抵抗性機序 / C型慢性肝炎 / インターロイキン6 / 治療抵抗性 / 肝発癌 / インターロイキン6 / コア変異株 / コア変異 / DAA製剤 / 小胞体ストレス
Outline of Final Research Achievements

Our previous study described the association of serum IL-6 levels and ER stress and drug-resistance using JFH1 genotype 2a cell culture system. Based on the pTPF1-M170T (LC011929), we constructed full-length 1b clones that expressed core mutant viruses which were clinically resistant to IFN. Although TPF1-M170T clones are not currently allowed in drug-screening tests, perhaps this unique character can assist in establishing the molecular mechanism of HCV replication. We conducted a cohort study to investigate whether serum IL-6 levels influenced treatment outcomes of TVR/PEG-IFN/RBV triple therapy. Our results suggest that baseline low levels of IL-6, as well as their transient increase and decline during early stage of treatment, are correlated to good response to treatment, whereas sustained high levels of serum IL-6 are correlated to treatment resistance in most cases. Taken together, serum IL-6 levels correlate with resistance to treatment also with DAA combination therapy.

Report

(4 results)
  • 2014 Annual Research Report   Final Research Report ( PDF )
  • 2013 Research-status Report
  • 2012 Research-status Report
  • Research Products

    (24 results)

All 2015 2014 2013 2012 Other

All Journal Article (8 results) (of which Peer Reviewed: 8 results,  Open Access: 3 results,  Acknowledgement Compliant: 1 results) Presentation (16 results)

  • [Journal Article] Impaired induction of IL28B and expression of IFNλ4 associated with non-response to interferon-based therapy in chronic hepatitis C.2015

    • Author(s)
      Murakawa M, Asahina Y, Nakagawa M, Sakamoto N, Nitta S, Kusano-Kitazume A, Watanabe T, Kawai-Kitahata F, Otani S, Taniguchi M, Goto F, Nishimura-Sakurai Y, Itsui Y, Azuma S, Kakinuma S, Watanabe M
    • Journal Title

      J Gastroenterol Hepatol

      Volume: 印刷中 Issue: 6 Pages: 1075-84

    • DOI

      10.1111/jgh.12902

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genome-wide association study identifies a PSMD3 variant associated with neutropenia in interferon-based therapy for chronic hepatitis C.2015

    • Author(s)
      Iio E, Matsuura K, Nishida N, Maekawa S, Enomoto N, Nakagawa M, Sakamoto N, Yatsuhashi H et al.
    • Journal Title

      Hum Genet

      Volume: 134 Issue: 3 Pages: 279-289

    • DOI

      10.1007/s00439-014-1520-7

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Serum granulysin levels as a predictor of serious telaprevir-induced dermatological reactions.2015

    • Author(s)
      Suda G, Yamamoto Y, Nagasaka A, Furuya K, Kudo M, Chuganji Y, Tsukuda Y, Tsunematsu S, Sato F, Terasita K, Nakai M, Horimoto H, Sho T, Natsuizaka M, Ogawa K, Ohnishi S, Chuma M, Fujita Y, Abe R, Taniguchi M, Nakagawa M, Asahina Y, Sakamoto N
    • Journal Title

      Hepatol Res

      Volume: 印刷中 Issue: 8 Pages: 837-45

    • DOI

      10.1111/hepr.12421

    • NAID

      120005820706

    • Related Report
      2014 Annual Research Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] α-fetoprotein levels afterinterferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C2013

    • Author(s)
      Asahina Y, Tsuchiya K, Nishimura T, Muraoka M, Suzuki Y, Tamaki N, Yasui Y, Hosokawa T, Ueda K, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Enomoto N, Nakagawa M, Kakinuma S, Watanabe M,Izumi N
    • Journal Title

      Hepatology

      Volume: (in press) Issue: 4 Pages: 1253-1262

    • DOI

      10.1002/hep.26442

    • Related Report
      2013 Research-status Report 2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Wnt5a Signaling Mediates Biliary Differentiation of Fetal Hepatic Stem/Progenitor Cells2013

    • Author(s)
      Kakinuma S, Kiyohashi K, Kamiya A, Sakamoto N, Nitta S, Yamanaka H, YoshinoK, Fujiki J, Murakawa M, Kusano-Kitazume A, Shimizu H, Okamoto R, Azuma S, Nakagawa M, Asahina Y, Tanimizu N, Kikuchi A, Nakauchi H, and *WatanabeM
    • Journal Title

      Hepatology

      Volume: (in press) Issue: 6 Pages: 2502-2513

    • DOI

      10.1002/hep.26293

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Hepatitis C virus NS4B protein targets STING and abrogates RIG-I-mediated type-I interferon-dependent innate immunity2013

    • Author(s)
      Nitta S, Sakamoto N, Nakagawa M, Kakinuma S, Mishima K, Kusano-kitazume A, Kiyohashi K, Murakawa M, Nishimura-Sakurai Y, Azuma S, Tasaka-Fujita M, asahina Y, Yoneyama M, Fujita T, Watanabe M
    • Journal Title

      Hepatology

      Volume: 57 Issue: 1 Pages: 46-58

    • DOI

      10.1002/hep.26017

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Association of ITPA gene variant and serum ribavirin concentration with blood cells decline in pegylated interferon-alfa plus ribavirin therapy for chronic hepatitis C.2013

    • Author(s)
      Nakagawa M, Sakamoto N, Watanabe T, Nishimura-Sakurai Y, Onozuka I, Azuma S, Kakinuma S, Nitta S, Kiyohashi K,Kusano-Kitazume A, Murakawa M, Yoshino K, Itsui Y, Tanaka Y, Mizokami M,Watanabe M, Ochanomizu Liver Conference Study Group
    • Journal Title

      Hepatol Int

      Volume: 7(1) Issue: 1 Pages: 153-161

    • DOI

      10.1007/s12072-012-9363-6

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Journal Article] Data mining model using simple and readily available factors could identify patients at high risk for hepatocellular carcinoma in chronic hepatitis C2012

    • Author(s)
      Kurosaki M, Sakamoto N, Nakagawa M, et al.
    • Journal Title

      J Hepatol

      Volume: 56(3) Issue: 3 Pages: 602-608

    • DOI

      10.1016/j.jhep.2011.09.011

    • Related Report
      2012 Research-status Report
    • Peer Reviewed
  • [Presentation] 難治性C型慢性肝炎に対するプロテアーゼ3剤併用療法の治療効果とDAA耐性変異の検討2015

    • Author(s)
      中川美奈、朝比奈靖浩, 渡辺守
    • Organizer
      第40回日本肝臓学会東部会
    • Place of Presentation
      京王プラザホテル(東京)
    • Year and Date
      2015-11-27
    • Related Report
      2014 Annual Research Report
  • [Presentation] C型慢性肝炎に対するDAAs併用療法の治療効果と耐性変異の検討2015

    • Author(s)
      中川美奈、朝比奈靖浩, 渡辺守
    • Organizer
      第101回日本消化器病学会総会
    • Place of Presentation
      仙台国際センター(仙台)
    • Year and Date
      2015-04-23
    • Related Report
      2014 Annual Research Report
  • [Presentation] Impact of host and therapeutic factors and resistant associated variants on response to interferon based- direct acting antiviral treatment in difficult-to-treat chronic hepatitis C patients.2014

    • Author(s)
      Mina Nakagawa, Yasuhiro Asahina, Miki Taniguchi, Takako Watanabe, Yuki Nishimura-Sakurai, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Yujiro Tanaka, Mamoru Watanabe
    • Organizer
      Annual Meeting of American Association for the Study of Liver Diseases
    • Place of Presentation
      Boston, USA
    • Year and Date
      2014-11-09 – 2014-11-11
    • Related Report
      2014 Annual Research Report
  • [Presentation] Gene alterations in β-catenin and p53/ cell cycle control pathway are closely associated with development and prognosis of hepatocellular carcinoma: Comprehensive analyses by next generation sequencing technology.2014

    • Author(s)
      Fukiko Kawai-Kitahata, Yasuhiro Asahina, Syun Kaneko, Hiroko Nagata, Fumio Goto, Satoshi Otani, Miki Taniguchi, Miyako Murakawa, Sayuri Nitta, Takako Watanabe, Megumi Tasaka-Fujita, Yasuhiro Itsui, Mina Nakagawa, Sei Kakinuma, Nobuyuki Enomoto, Mamoru Watanabe
    • Organizer
      Annual Meeting of American Association for the Study of Liver Diseases
    • Place of Presentation
      Boston, USA
    • Year and Date
      2014-11-09 – 2014-11-11
    • Related Report
      2014 Annual Research Report
  • [Presentation] C型慢性肝炎に対するインターフェロンをベーストしたプロテアーゼ3剤併用療法の治療効果とDAA耐性変異の検討2014

    • Author(s)
      中川美奈、朝比奈靖浩, 渡辺守
    • Organizer
      第18回日本肝臓学会大会
    • Place of Presentation
      ポートピアホテル(神戸)
    • Year and Date
      2014-10-23
    • Related Report
      2014 Annual Research Report
  • [Presentation] NS3およびNS5A阻害剤耐性変異とシメプレビルおよびテラプレビル3剤併用療法の治療効果2014

    • Author(s)
      朝比奈靖浩, 中川美奈、渡辺守
    • Organizer
      第50回日本肝臓学会総会
    • Place of Presentation
      ホテルニューオータニ(東京)
    • Year and Date
      2014-05-29
    • Related Report
      2014 Annual Research Report
  • [Presentation] インターフェロン治療後の線維化マーカーの推移と発癌リスクの検討2014

    • Author(s)
      中川美奈、朝比奈靖浩, 渡辺守
    • Organizer
      第50回日本肝臓学会総会
    • Place of Presentation
      ホテルニューオータニ(東京)
    • Year and Date
      2014-05-29
    • Related Report
      2014 Annual Research Report
  • [Presentation] 次世代プロテアーゼ阻害剤併用3剤治療の適応症例の検討2014

    • Author(s)
      中川美奈、朝比奈靖浩, 渡辺守
    • Organizer
      第100回日本消化器病学会総会
    • Place of Presentation
      東京国際フォーラム(東京)
    • Year and Date
      2014-04-24
    • Related Report
      2014 Annual Research Report
  • [Presentation] 慢性肝疾患における肝細胞癌とIL-6の関連

    • Author(s)
      谷口未樹、中川美奈
    • Organizer
      第49回日本肝臓学会総会
    • Place of Presentation
      東京
    • Related Report
      2013 Research-status Report
  • [Presentation] 難治性C型慢性肝炎におけるテラプレビル3剤併用療法の効果と安全性の検討

    • Author(s)
      朝比奈靖浩, 中川美奈、渡辺守
    • Organizer
      第99回日本消化器病学会総会
    • Place of Presentation
      鹿児島
    • Related Report
      2013 Research-status Report 2012 Research-status Report
  • [Presentation] 難治性C型慢性肝炎におけるテラプレビル3剤併用療法の有用性の検討

    • Author(s)
      朝比奈靖浩, 中川美奈、渡辺守
    • Organizer
      第49回日本肝臓学会総会
    • Place of Presentation
      東京
    • Related Report
      2013 Research-status Report
  • [Presentation] 難治性C型慢性肝炎におけるIFN応答性に関与する要因とテラプレビル3剤併用療法の効果

    • Author(s)
      中川美奈、坂本直哉、朝比奈靖浩
    • Organizer
      第16回日本肝臓学会大会
    • Place of Presentation
      神戸
    • Related Report
      2012 Research-status Report
  • [Presentation] C型肝疾患コホートにおける宿主遺伝子多型およびHCV遺伝子構造と予後との関連

    • Author(s)
      中川美奈、坂本直哉、朝比奈靖浩
    • Organizer
      第16回日本肝臓学会大会
    • Place of Presentation
      神戸
    • Related Report
      2012 Research-status Report
  • [Presentation] 宿主遺伝子情報に基づいたC型慢性肝炎の最適な治療法の選択

    • Author(s)
      中川美奈、坂本直哉、渡辺守
    • Organizer
      第48回日本肝臓学会総会
    • Place of Presentation
      金沢
    • Related Report
      2012 Research-status Report
  • [Presentation] 慢性肝疾患における肝細胞癌とIL-6の関連

    • Author(s)
      中川美奈、坂本直哉、渡辺守
    • Organizer
      第48回日本肝臓学会総会
    • Place of Presentation
      金沢
    • Related Report
      2012 Research-status Report
  • [Presentation] 宿主遺伝子情報に基づいたC型慢性肝炎治療の効果・安全性の最適化

    • Author(s)
      中川美奈、坂本直哉、渡辺守
    • Organizer
      第98回日本消化器病学会総会
    • Place of Presentation
      東京
    • Related Report
      2012 Research-status Report

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Published: 2013-05-31   Modified: 2019-07-29  

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