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Development of novel and safe immune therapy to achieve hepatitis B

Research Project

Project/Area Number 16H05288
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Gastroenterology
Research InstitutionNagoya City University

Principal Investigator

TANAKA Yasuhito  名古屋市立大学, 大学院医学研究科, 教授 (90336694)

Co-Investigator(Kenkyū-buntansha) 岸 裕幸  富山大学, 大学院医学薬学研究部(医学), 教授 (60186210)
Research Collaborator ISOGAWA masanori  
SATO yusuke  
Project Period (FY) 2016-04-01 – 2019-03-31
Project Status Completed (Fiscal Year 2018)
Budget Amount *help
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2018: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2017: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
Fiscal Year 2016: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
KeywordsHBV / B細胞応答 / 抗ウイルス療法 / 新規免疫治療法 / siRNA / MEND / 新規免疫療法
Outline of Final Research Achievements

Persistent infection with hepatitis B virus (HBV) causes cirrhosis・hepatocellular carcinoma as well as HBV reactivation, and its termination is urgently needed. Here, we attempted the production and optimization of humanized anti-CD40 antibody that possesses an anti-virus effect. We first evaluated the impact of CD40 activation on HBV-specific T cell receptor transgenic CD8+ T cells that were adoptively transferred into HBV transgenic mice. We found that treatment of HBV transgenic mice with CD40 antibody during the early phase of T cell responses restored functionally of HBV-specific CD8+ T cells and reduced HBV-mRNA expression levels, while the same treatment during the late phase had no impact on these parameters. We also established an ELISPOT assay system that enables us to analyze HBsAg-specific B cell responses in the human peripheral blood.

Academic Significance and Societal Importance of the Research Achievements

現在、HBV持続感染を治癒する有効な治療法はなく、HBV持続感染患者への精神的・経済的な負担は計り知れない。HBVの排除には宿主免疫応答の活性化が必須とされているが、最適なアプローチは全く明らかにされていない。本研究成果から、CD40抗体の投与による免疫賦活効果はHBV特異的CD8+T細胞の分化段階に依存することが明らかになった。さらに、本研究で構築したHBsAg特異的B細胞応答の解析システムにより、CD40抗体などの免疫賦活がB細胞応答に及ぼす影響をより正確に評価できるようになった。これらの結果はHBVに対する免疫治療開発を促進し、HBV持続感染による社会的負担の軽減につながると考えられる。

Report

(4 results)
  • 2018 Annual Research Report   Final Research Report ( PDF )
  • 2017 Annual Research Report
  • 2016 Annual Research Report
  • Research Products

    (28 results)

All 2019 2018 2017 2016

All Journal Article (9 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 7 results,  Open Access: 2 results) Presentation (19 results) (of which Int'l Joint Research: 12 results)

  • [Journal Article] 消化器内科学 Functional cureをめざすB型肝炎治療の近未来2019

    • Author(s)
      五十川正記、田中靖人
    • Journal Title

      医学のあゆみ

      Volume: 268(4) Pages: 282-283

    • Related Report
      2018 Annual Research Report
  • [Journal Article] Intrahepatic Cross-Presentation and Hepatocellular Antigen Presentation Play Distinct Roles in the Induction of HBV-Specific CD8+ T Cell Responses2018

    • Author(s)
      Murata Yasuhiro, Kawashima Keigo, Sheikh Knvul, Tanaka Yasuhito, Isogawa Masanori
    • Journal Title

      Journal of Virology

      Volume: 92 (21) Issue: 21 Pages: 00920-18

    • DOI

      10.1128/jvi.00920-18

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Type I Interferon Signaling Prevents Hepatitis B Virus-Specific T Cell Responses by Reducing Antigen Expression2018

    • Author(s)
      Kawashima Keigo, Isogawa Masanori, Hamada-Tsutsumi Susumu, Baudi Ian, Saito Satoru, Nakajima Atsushi, Tanaka Yasuhito
    • Journal Title

      Journal of Virology

      Volume: 92 (23) Issue: 23 Pages: 01099-18

    • DOI

      10.1128/jvi.01099-18

    • Related Report
      2018 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] B型肝炎に対する免疫治療の展望2018

    • Author(s)
      五十川正記、田中靖人
    • Journal Title

      Medical Science Digest

      Volume: 44(7) Pages: 344-349

    • Related Report
      2018 Annual Research Report
  • [Journal Article] High levels of serum Mac-2-binding protein glycosylation isomer (M2BPGi) predict the development of hepatocellular carcinoma in hepatitis B patients treated with nucleot(s)ide analogues.2018

    • Author(s)
      Shinkai N, Nojima M, Iio E, Matsunami K, Toyoda H, Murakami S, Inoue T, Ogawa S, Kumada T, Tanaka Y.
    • Journal Title

      J Gastroenterol.

      Volume: 印刷中 Issue: 7 Pages: 883-889

    • DOI

      10.1007/s00535-017-1424-0

    • Related Report
      2017 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Molecular epidemiology of co-infection with hepatitis B virus and human immunodeficiency virus (HIV) among adult patients in Harare, Zimbabwe2017

    • Author(s)
      Baudi I, Iijima S, Chin'ombe N, Mtapuri-Zinyowera S, Murakami S, Isogawa M, Hachiya A, Iwatani Y, and Tanaka Y
    • Journal Title

      Journal of Medical Virology

      Volume: 89 Issue: 2 Pages: 257-266

    • DOI

      10.1002/jmv.24641

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Novel monitoring of hepatitis B reactivation based on ultra-high sensitive hepatitis B surface antigen assay2017

    • Author(s)
      Shinkai N, Kusumoto S, Murakami S, Ogawa S, Ri M, Matsui T, Tamori A, Toyoda H, Ishida T, Iida S, Tanaka Y.
    • Journal Title

      Liver Int.

      Volume: 印刷中 Issue: 8 Pages: 1138-1147

    • DOI

      10.1111/liv.13349

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Longitudinal profiles of highly sensitive hepatitis B surface antigen levels: re-evaluation of HBsAg seroclearance.2016

    • Author(s)
      Seto WK, Tanaka Y, Wong DK, Shinkai N, Cheung KS, Liu KS, Fung J, Lai CL, Yuen MF.
    • Journal Title

      Liver Int.

      Volume: 36 Issue: 5 Pages: 642-650

    • DOI

      10.1111/liv.12980

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Hepatitis B virus and its sexually transmitted infection - an update2016

    • Author(s)
      Inoue T, Tanaka Y.
    • Journal Title

      microbial cell.

      Volume: 3 Issue: 9 Pages: 420-437

    • DOI

      10.15698/mic2016.09.527

    • Related Report
      2016 Annual Research Report
    • Peer Reviewed
  • [Presentation] Activation of type I interferon signaling is required for the induction of functional HBV-specific CD8 T cells,2018

    • Author(s)
      Kawashima K,Isogawa M,Saito S,Nakajima A,Tanaka Y,
    • Organizer
      The 2018 International HBV Meeting The Molecular Biology of Hepatitis B Viruses
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Ifnα Directly Induces Apoptosis in Hepatocytes That Accumulate the Large Hepatitis B Surface Antigen,2018

    • Author(s)
      Baudi I, Isogawa M, Kawashima K, Tanaka Y,
    • Organizer
      The 69th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD2018)
    • Related Report
      2018 Annual Research Report
    • Int'l Joint Research
  • [Presentation] HBV特異的CD8+T細胞応答誘導における肝細胞の役割2018

    • Author(s)
      五十川正記,、村田泰洋、 田中靖人
    • Organizer
      第32回肝類洞壁細胞研究会学術集会
    • Related Report
      2018 Annual Research Report
  • [Presentation] Reduction of hepatitis B virus (HBV) gene expression in the liver induces functional HBV-specific CD8 T cell responses without liver disease2017

    • Author(s)
      Kawashima K, Isogawa M, Saito S, Tanaka Y.
    • Organizer
      The 26th Conference of the Asian Pacific Association for the Study of the Liver (APASL Annual Meeting 2017)
    • Place of Presentation
      上海(中国)
    • Year and Date
      2017-02-15
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Clearance rate of hepatitis B virus (HBV) is associated with the level of the core antigen expression that determines the magnitude of HBV-specific CD8 T cell responses2017

    • Author(s)
      Isogawa M, Kawashima K, Tsutsumi-hamada S, Tanaka Y.
    • Organizer
      The 26th Conference of the Asian Pacific Association for the Study of the Liver (APASL Annual Meeting 2017)
    • Place of Presentation
      上海(中国)
    • Year and Date
      2017-02-15
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Type I interferon signaling prevents hepatitis B virus-specific T cell responses.2017

    • Author(s)
      Kawashima K, Isogawa M, Tsutsumi S, Saito S, Nakajima A, Tanaka Y.
    • Organizer
      The 2017 International HBV Meeting.
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Hepatitis B Virus-specific T Cell Responses Are Regulated by Type I Interferon Signaling and Correlated with Intrahepatic Antigen Expression.2017

    • Author(s)
      Kawashima K, Isogawa M, Hamada-Tsutsumi S, Saito S, Tanaka Y.
    • Organizer
      The 68th Annual Meeting of the American Association for the Study of Liver Diseases.
    • Related Report
      2017 Annual Research Report
    • Int'l Joint Research
  • [Presentation] I型インターフェロンシグナルは肝臓内HBV特異的CD8+T細胞応答を阻害する.2017

    • Author(s)
      河島 圭吾, 五十川 正記, 田中 靖人.
    • Organizer
      第103回日本消化器病学会総会.
    • Related Report
      2017 Annual Research Report
  • [Presentation] HBV 特異的CD8+T 細胞応答によるHBV 排除への試み2016

    • Author(s)
      河島圭吾, 五十川正記, 田中靖人.
    • Organizer
      第41回日本肝臓学会東部会
    • Place of Presentation
      京王プラザホテル(東京都・新宿区)
    • Year and Date
      2016-12-08
    • Related Report
      2016 Annual Research Report
  • [Presentation] Silencing hepatitis B virus (HBV) gene expression in the liver by RNAi prevents HBV-specific CD8 T cell exhaustion2016

    • Author(s)
      Kawashima K, Isogawa M, Saito S, Tanaka Y.
    • Organizer
      The 67th Annual Meeting of the American Association for the Study of Liver Diseases(AASLD2016)
    • Place of Presentation
      ボストン(アメリカ)
    • Year and Date
      2016-11-11
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The hepatitis B virus (HBV) core antigen expression level determines the rate of CD8 T cell mediated viral clearance2016

    • Author(s)
      Isogawa M, Kawashima K, Tsutsumi S, Tanaka Y.
    • Organizer
      The 67th Annual Meeting of the American Association for the Study of Liver Diseases(AASLD2016)
    • Place of Presentation
      ボストン(アメリカ)
    • Year and Date
      2016-11-11
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] HBV抗原抑制は機能的なHBV特異的CD8+T細胞応答誘導による肝障害を軽減する~HBV排除を目指して2016

    • Author(s)
      河島圭吾, 五十川正記, 田中靖人.
    • Organizer
      第20回日本肝臓学会大会
    • Place of Presentation
      神戸国際展示場(兵庫県・神戸市)
    • Year and Date
      2016-11-03
    • Related Report
      2016 Annual Research Report
  • [Presentation] Hepatitis B virus (HBV) antigen suppression prevents HBV-specific CD8 T cell exhaustion2016

    • Author(s)
      kawashima K, Isogawa M, Saito S, Nakajima A, Tanaka Y.
    • Organizer
      Asian Pacific Digestive Week 2016 (APDW 2016)
    • Place of Presentation
      神戸コンベンションセンター(兵庫県・神戸市)
    • Year and Date
      2016-11-02
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Suppression of the hepatitis B virus (HBV) antigen expression in the liver prevents HBV-specific CD8 T cell exhaustion2016

    • Author(s)
      Kawashima K, Isogawa M, Saito S, Nakajima A, Tanaka Y.
    • Organizer
      2016 International HBV Meeting on the Molecular Biology of Hepatitis B Viruses
    • Place of Presentation
      ソウル(韓国)
    • Year and Date
      2016-09-21
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] 異なるHBV遺伝子型によるHBV抗原遷延化率の違い~肝臓内CD8+T細胞応答およびコア抗原発現量の相関性2016

    • Author(s)
      河島圭吾, 五十川正記, 堤進, 村上周子, 斉藤聡, 中島淳, 田中靖人.
    • Organizer
      第52回日本肝臓学会総会
    • Place of Presentation
      東京ベイ幕張ホール(千葉県・千葉市)
    • Year and Date
      2016-05-19
    • Related Report
      2016 Annual Research Report
  • [Presentation] 肝臓内B型肝炎ウイルス(HBV)抗原抑制による機能的なHBV特異的CD8+T細胞応答の誘導2016

    • Author(s)
      河島圭吾, 五十川正記, 田中靖人.
    • Organizer
      第26回抗ウイルス療法学会総会
    • Place of Presentation
      名古屋市立大学(愛知県・名古屋市)
    • Year and Date
      2016-05-13
    • Related Report
      2016 Annual Research Report
  • [Presentation] 肝臓内HBV抗原抑制によるHBV特異的エフェクターCD8+T細胞応答の誘導2016

    • Author(s)
      河島圭吾, 五十川正記, 田中靖人.
    • Organizer
      第102回日本消化器病学会総会
    • Place of Presentation
      京王プラザホテル(東京都・新宿区)
    • Year and Date
      2016-04-21
    • Related Report
      2016 Annual Research Report
  • [Presentation] Differential core antigen expressions between hepatitis B virus genotypes determine the magnitude of virus specific CD8 T cell responses and the rate of viral clearance2016

    • Author(s)
      Kawashima K, Isogawa M, Tsutsumi S, Murakami S, Saito S, Nakajima A, Tanaka Y.
    • Organizer
      4th Taiwan-Korea-Japan Research Symposium on Hepatitis B Virus
    • Place of Presentation
      台北(台湾)
    • Year and Date
      2016-04-09
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Endogenous antigen presentation by hepatocytes plays an essential role in the induction of HBV-specific CD8+ T cell responses2016

    • Author(s)
      Isogawa M, Murata Y, Kawashima K, Tanaka Y.
    • Organizer
      4th Taiwan-Korea-Japan Research Symposium on Hepatitis B Virus
    • Place of Presentation
      台北(台湾)
    • Year and Date
      2016-04-09
    • Related Report
      2016 Annual Research Report
    • Int'l Joint Research

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Published: 2016-04-21   Modified: 2020-03-30  

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