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治療不応性に関わる自然免疫促進及び抑制系IFNシグナル伝達とHCV逃避機構の解析

Research Project

Project/Area Number 24890058
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeSingle-year Grants
Research Field Gastroenterology
Research InstitutionTokyo Medical and Dental University

Principal Investigator

朝比奈 靖浩  東京医科歯科大学, 医歯(薬)学総合研究科, その他 (00422692)

Project Period (FY) 2012-08-31 – 2014-03-31
Project Status Declined (Fiscal Year 2013)
Budget Amount *help
¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2012: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Keywords内科 / HCV / 自然免疫 / IFNλ / RIG-I
Research Abstract

IL28B SNPとC型慢性肝炎治療効果は関連するが、近年標準治療となったテラプレビル3剤治療においては、IFNへの反応性が治療効果を規定する。我々はこのIFN不応例の病態を解明するため、C型慢性肝炎患者末梢血リンパ球(PBMC)におけるIFNλおよび自然免疫関連分子の発現を解析しIFN応答性との関連を調べるとともに、SNPが治療効果を規定する機序についてin vitroでの検討を推進している。本研究では、臨床的検体を用いた自然免疫型遺伝子発現とIFN不応性分子機構の解明として、Peg-IFN/RBV治療を施行したC型慢性肝炎患者50例(rs8099917 TT:major群27名、TG/GG:minor群23名)を対象とした。PBMCを採取後IFNα+poly I:刺激を行い、IFNλを含む自然免疫関連分子の発現量を治療効果(Virological Responder(VR) vs NR)との関連を解析した。その結果IFNα+poly I:C刺激によるIL28Bの発現誘導はmajor・minorいずれにおいてもNRがVRに比べ低値であり、IL28B発現誘導と前治療効果の関連が見られた(P=0.003)。そこで、IL28B majorまたはminorの患者由来のDNA配列を有するIL28B reporter plasmidを作成し、自然免疫系シグナル刺激を行った際のIL28B転写活性を解析した。Promoter活性はminor typeがmajorに比し低値であり、rs8099917と連鎖する近位SNPによりIL28B転写活性に差異が生じる可能性が示唆された。従って、IFN投与時のPMBCにおけるIL28B産生能はIFN-based therapyの治療効果を規定することが示唆された。またIL28B SNPが治療効果を規定する機序の一つとして転写活性の差が考えられた。

Current Status of Research Progress
Reason

翌年度、交付申請を辞退するため、記入しない。

Strategy for Future Research Activity

翌年度、交付申請を辞退するため、記入しない。

Report

(1 results)
  • 2012 Annual Research Report
  • Research Products

    (26 results)

All 2013 2012 2011

All Journal Article (12 results) (of which Peer Reviewed: 11 results) Presentation (10 results) (of which Invited: 1 results) Book (4 results)

  • [Journal Article] Inhibition of hepatocellular carcinoma by PegIFNα2a in patients with chronic hepatitis C: a nationwide multi-center cooperative study.2013

    • Author(s)
      Izumi N, Asahina Y, Kumada H et al
    • Journal Title

      J Gastroenterol

      Volume: 48 Issue: 3 Pages: 382-390

    • DOI

      10.1007/s00535-012-0641-9

    • Related Report
      2012 Annual Research 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 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Noninvasive estimation of fibrosis progression overtime using the FIB-4 index in chronic hepatitis C.2013

    • Author(s)
      Tamaki N, Asahina Y, Izumi N et al
    • Journal Title

      J Viral Hepat

      Volume: 20 Issue: 1 Pages: 72-76

    • DOI

      10.1111/j.1365-2893.2012.01635.x

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Model incorporating the ITPA genotype identifies patients at high risk of anemia and treatment failure with pegylated-interferon plus ribavirin therapy for chronic hepatitis C.2013

    • Author(s)
      Kurosaki M, Sakamoto N, Asahina Y, Izumi N et al
    • Journal Title

      J Med Virol

      Volume: 85 Issue: 3 Pages: 449-458

    • DOI

      10.1002/jmv.23497

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Virological response and safety of 24-week telaprevir alone in Japanese patients infected with hepatitis C virus subtype 1b.2013

    • Author(s)
      Toyota J, Asahina Y, Kumada H et al
    • Journal Title

      J Viral Hepat

      Volume: 20 Issue: 3 Pages: 167-173

    • DOI

      10.1111/j.1365-2893.2012.01640.x

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Wnt5a signaling mediates biliary differentiation of fetal hepatic stem/progenitor cells2013

    • Author(s)
      Kiyohashi K
    • Journal Title

      Hepatology

      Volume: in press

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] α-fetoprotein levels after interferon therapy and risk of hepatocarcinogenesis in chronic hepatitis C2013

    • Author(s)
      Asahina Y
    • Journal Title

      Hepatology

      Volume: in press

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Impaired brain activity in cirrhotic patients with minimal hepatic encephalopathy: evaluation by near infrared spectroscopy2013

    • Author(s)
      Nakanishi H
    • Journal Title

      Hepatol Res

      Volume: 43 Pages: 1-34

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Guidelines for the Management of Hepatitis C Virus Infection.2013

    • Author(s)
      Asahina Y
    • Journal Title

      Hepatol Res

      Volume: in press

    • NAID

      130003384472

    • Related Report
      2012 Annual Research Report
  • [Journal Article] No association for Chinese HBV-related hepatocellular carcinoma susceptibility SNP in other East Asian populations.2012

    • Author(s)
      Sawai H, Asahina Y, Tokunaga K et al
    • Journal Title

      BMC Med Genet

      Volume: 13 Issue: 1 Pages: 47-47

    • DOI

      10.1186/1471-2350-13-47

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Genome-wide association study confirming association of HLA-DP with protection against chronic hepatitis B and viral clearance in Japanese and Korean.2012

    • Author(s)
      Nishida N, Asahina Y, Mizokami M et al
    • Journal Title

      PLoS One

      Volume: 7 Issue: 6 Pages: 1-8

    • DOI

      10.1371/journal.pone.0039175

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Association of gene expression involving innate immunity and genetic variation in IL28B with antiviral response2011

    • Author(s)
      Asahina Y, Sakamoto N, et al
    • Journal Title

      Hepatology

      Volume: 55(1) Issue: 1 Pages: 20-29

    • DOI

      10.1002/hep.24623

    • Related Report
      2012 Annual Research Report
    • Peer Reviewed
  • [Presentation] Serum interleukin-6 levels during treatment correlate with resistance to telaprevir-based triple therapy in chronic hepatitis C2013

    • Author(s)
      Asahina Y
    • Organizer
      EASL: The international liver congress 2013
    • Place of Presentation
      Amsterdam
    • Related Report
      2012 Annual Research Report
  • [Presentation] Association of Gene Expression Involving Innate Immunity and IFN Signaling with Genetic Variation in IL28B in Patients with Chronic Hepatitis C.2012

    • Author(s)
      Asahina Y
    • Organizer
      The 10th JSH Single Topic Conference
    • Place of Presentation
      Tokyo
    • Related Report
      2012 Annual Research Report
    • Invited
  • [Presentation] HCV-NS4B Protein Binds STING and Blocks the RIG-I Mediated IFN Pathway.2012

    • Author(s)
      Nitta S
    • Organizer
      The 10th JSH Single Topic Conference
    • Place of Presentation
      Tokyo
    • Related Report
      2012 Annual Research Report
  • [Presentation] Discovery of N-(morpholine-4-carbonyloxy) amidine compounds as potent inhibitors against hepatitis C virus replication.2012

    • Author(s)
      Akiko Kusano-Kitazume
    • Organizer
      The 10th JSH Single Topic Conference
    • Place of Presentation
      Tokyo
    • Related Report
      2012 Annual Research Report
  • [Presentation] Impaired induction of IL28B expression in PBMC is associated with null response to interferon therapy in chronic hepatitis C.2012

    • Author(s)
      Murakawa M
    • Organizer
      19th International Symposium on Hepatitis C Virus and Related Viruses
    • Place of Presentation
      Venice
    • Related Report
      2012 Annual Research Report
  • [Presentation] HCV-NS4B blocks the RIG-I mediated IFN pathway through targeting of STING.2012

    • Author(s)
      Nitta S
    • Organizer
      19th International Symposium on Hepatitis C Virus and Related Viruses
    • Place of Presentation
      Venice
    • Related Report
      2012 Annual Research Report
  • [Presentation] Imparied IL28B gene induction and poor IL28B promoter activity influenced by the IL28B minor allele are closely associated with a null response to interferon in chronic hepatitis C patients.2012

    • Author(s)
      Asahina Y
    • Organizer
      AASLD The Liver Meeting 2012
    • Place of Presentation
      Boston
    • Related Report
      2012 Annual Research Report
  • [Presentation] Risk factors for exceeding the Milan criteria following successful radiofrequency ablation in patients with early stage hepatocellular carcinoma: determination of patients requiring early transplantation or new adjuvant therapy2012

    • Author(s)
      Tsuchiya K
    • Organizer
      AASLD The Liver Meeting 2012
    • Place of Presentation
      Boston
    • Related Report
      2012 Annual Research Report
  • [Presentation] Reduced organic anion transporter 2 expression is associated with a high risk for hepatocellulare carcinoma in chronic hepatitis C patients: a propensity score-matched study.2012

    • Author(s)
      Yasui Y
    • Organizer
      AASLD The Liver Meeting 2012
    • Place of Presentation
      Boston
    • Related Report
      2012 Annual Research Report
  • [Presentation] Antiviral effects and action mechanisms of novel N-(morpholine-4-carbonyloxy) amidine compaunds against hepatitis C virus.2012

    • Author(s)
      Kusano-Kitazume A
    • Organizer
      AASLD The Liver Meeting 2012
    • Place of Presentation
      Boston
    • Related Report
      2012 Annual Research Report
  • [Book] 肝癌治療実践のKnack & Pitfalls RFAのoutcome診療ガイドラインに沿った肝癌治療の要点と盲点2013

    • Author(s)
      高山忠利、泉並木、朝比奈靖浩
    • Publisher
      文光堂
    • Related Report
      2012 Annual Research Report
  • [Book] 肝臓病診療 ゴールデンハンドブック 改訂第2版2012

    • Author(s)
      泉並木、朝比奈靖浩
    • Publisher
      南江堂
    • Related Report
      2012 Annual Research Report
  • [Book] 肝炎ウイルスーB型・C型2012

    • Author(s)
      熊田博光、朝比奈靖浩
    • Publisher
      医薬ジャーナル社
    • Related Report
      2012 Annual Research Report
  • [Book] 臨床検査のガイドライン2012

    • Author(s)
      日本臨床検査医学会ガイドライン作成委員会、朝比奈靖浩
    • Publisher
      株式会社宇宙堂八木書店
    • Related Report
      2012 Annual Research Report

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Published: 2012-11-27   Modified: 2019-07-29  

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