Induction of hepatitis B virus specific T cell responses by activating innate immune response

• Project/Area Number: 26461015
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Nagoya City University
• Principal Investigator: ISOGAWA Masanori 名古屋市立大学, 大学院医学研究科, 助教 (50723201)
• Co-Investigator(Renkei-kenkyūsha): Tanaka Yasuhito 名古屋市立大学, 大学院医学研究科, 教授 (90336694)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); 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: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: B型肝炎ウイルス / HBV特異的CD8+T細胞 / 抗原提示 / 活性化樹状細胞

Outline of Final Research Achievements

In this study, we determined whether endogenous antigen presentation by hepatocytes or cross-presentation by bone marrow derived cells is more important in the induction of hepatitis B virus (HBV)-specific T cell responses. To do so, we employed transgenic mice that replicate HBV at high level in the liver (HBV-Tg mice) to generate HBV-Tg mice whose MHC class I expression is absent on bone marrow derived cells, or parenchymal cells. We then adoptively transferred HBV-specific T cells, and monitored their responsiveness. Our data suggest that cross-presentation by hematopoietic cells is required for the optimum expansion of HBV-specific T cells, but endogenous antigen presentation by non-hematopoietic cells, presumably hepatocytes, is far more essential in the expansion and cytolytic differentiation of HBV-specific T cells.

Research Products

• [Journal Article] Molecular epidemiology of co-infection with hepatitis B virus and human immunodeficiency virus (HIV) among adult patients in Harare, Zimbabwe (2017)
  • 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
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] A new class of hepatitis B and D virus entry inhibitors, proanthocyanidin and its analogs, that directly act on the viral large surface proteins. (2017)
  • Author(s): Tsukuda S, Watashi K, Hojima T, Isogawa M, Iwamoto M, Omagari K, Suzuki R, Aizaki H, Kojima S, Sugiyama M, Saito A, Tanaka Y, Mizokami M, Sureau C, Wakita T
  • Journal Title: Hepatology Volume: 65 Issue: 4 Pages: 1104-1116
  • DOI: 10.1002/hep.28952
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ｂ型肝炎治療不応例における新規Entecavir耐性変異（rtA186T）の同定. (2016)
  • Author(s): 林佐奈衣, 村上周子, 尾曲克己, 松居剛志, 飯尾悦子, 五十川正記, 渡邊綱正, 狩野吉康, 田中靖人.
  • Journal Title: NAGOYA MEDICAL JOURNAL（名古屋市立大学医学会雑誌） Volume: 55(1) Pages: 35-42
• [Journal Article] 新規核酸アナログ4'-C-cyano-2-amino-2'-deoxyadenosine、4'-C-cyano-2'-deoxyguanosineは薬剤耐性B型肝炎ウイルス変異株に対して有効である. (2016)
  • Author(s): 林佐奈衣, 高松悠樹, 前田賢次, 村上周子, 尾曲克己, 松居剛志, 五十川正記, 渡邊綱正, 狩野吉康, 向後悟, 満屋裕明, 田中靖人.
  • Journal Title: 肝臓 Volume: 57(6) Pages: 299-301
  • NAID: 130005160949
  • Peer Reviewed
• [Journal Article] Host genetic variants influencing the clinical course of Hepatitis B virus infection. (2016)
  • Author(s): Matsuura K, Isogawa M, Tanaka Y.
  • Journal Title: J Med Virol. Volume: 88(3) Issue: 3 Pages: 371-9
  • DOI: 10.1002/jmv.24350
  • Int'l Joint Research
• [Journal Article] Host-virus interactions in hepatitis B virus infection. (2015)
  • Author(s): Guidotti LG, Isogawa M, Chisari FV.
  • Journal Title: Curr Opin Immunol. Volume: 36 Pages: 61-6
  • DOI: 10.1016/j.coi.2015.06.016
  • Int'l Joint Research
• [Journal Article] Immunosurveillance of the liver by intravascular effector CD8(+) T cells. (2015)
  • Author(s): Guidotti LG, Inverso D, Sironi L, Di Lucia P, Fioravanti J, Ganzer L, Fiocchi A, Vacca M, Aiolfi R, Sammicheli S, Mainetti M, Cataudella T, Raimondi A, Gonzalez-Aseguinolaza G, Protzer U, Ruggeri ZM, Chisari FV, Isogawa M, Sitia G, Iannacone M.
  • Journal Title: Cell Volume: 161(3) Issue: 3 Pages: 486-500
  • DOI: 10.1016/j.cell.2015.03.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Characterization of novel entecavir resistance mutations. (2015)
  • Author(s): Hayashi S, Murakami S, Omagari K, Matsui T, Iio E, Isogawa M, Watanabe T, Karino Y, Tanaka Y.
  • Journal Title: J Hepatol. Volume: 63(3) Issue: 3 Pages: 546-53
  • DOI: 10.1016/j.jhep.2015.03.020
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Immunobiology of hepatitis B virus infection. (2015)
  • Author(s): Isogawa M, Tanaka Y.
  • Journal Title: Hepatology Research Volume: 45 Issue: 2 Pages: 179-189
  • DOI: 10.1111/hepr.12439
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Hepatocellular carcinoma-associated core N51H mutation with BCP PC mutations in HBV genotype F1b enhances infectivity and up-regulates C-Myc and GAB2 (2016)
  • Author(s): Hayashi S, Khan AA, Ogawa K, Kawashima K, Simons-Petrusa B, Homan CE, McMahon BJ, Murakami S, Iijima S, Isogawa M, Watanabe T, Tanaka Y
  • Organizer: The 67th Annual Meeting of the American Association for the Study of Liver Diseases(AASLD2016)
  • Place of Presentation: John B. Hynes Veterans Memorial Convention Center, The United States of America, Boston,
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Silencing hepatitis B virus (HBV) gene expression in the liver by RNAi prevents HBV-specific CD8 T cell exhaustion (2016)
  • 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: John B. Hynes Veterans Memorial Convention Center, The United States of America, Boston,
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] The hepatitis B virus (HBV) core antigen expression level determines the rate of CD8 T cell mediated viral clearance (2016)
  • 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: John B. Hynes Veterans Memorial Convention Center, The United States of America, Boston,
  • Year and Date: 2016-11-11
  • Int'l Joint Research
• [Presentation] Hepatitis B virus (HBV) antigen suppression prevents HBV-specific CD8 T cell exhaustion (2016)
  • Author(s): Kawashima K, Isogawa M, Saito S, Nakajima A, Tanaka Y
  • Organizer: Asian Pacific Digestive Week 2016 (APDW 2016)
  • Place of Presentation: Kobe Convention Center (International Exhibition Center), Hyogo, Kobe
  • Year and Date: 2016-11-02
  • Int'l Joint Research
• [Presentation] Novel 4'-modified nucleoside analogs,CAdA and CdG，strongly suppress the replication of wild-type hepatitis B virus and drug-resistant mutants (2016)
  • Author(s): Hayashi S, Takamatsu Y, Maeda K, Murakami S, Omagari K, Matsui T, Isogawa M, Watanabe T, Karino Y, Kohgo S, Mitsuya H, Tanaka Y
  • Organizer: 2016 International HBV Meeting on the Molecular Biology of Hepatitis B Viruses
  • Place of Presentation: Centennial Concert Hall, Yonsei University, Korea, Seoul
  • Year and Date: 2016-09-21
  • Int'l Joint Research
• [Presentation] Proanthocyanidin and its analogs are new class of HBV and HDV entry inhibitors that target the viral preS1 region (2016)
  • Author(s): Tsukuda S, Watashi K, Hojima T, Isogawa M, Iwamoto M, Suzki R, Aizaki H, Kojima S, Sugiyama M, Saito A, Tanaka Y, Mizokami M, Wakita T
  • Organizer: 2016 International HBV Meeting on the Molecular Biology of Hepatitis B Viruses
  • Place of Presentation: Centennial Concert Hall, Yonsei University, Korea, Seoul
  • Year and Date: 2016-09-21
  • Int'l Joint Research
• [Presentation] Retinoic acid inducible gene-I like receptors (RLRs) stimulation suppresses hepatitis B virusn (HBV) replication and induces cytotolytic ability of HBV-specific CD8 T cells more efficiently than Toll like receptor 3 stimulation (2016)
  • Author(s): Kawashima K, Isogawa M, Tanaka Y
  • Organizer: 2016 International HBV Meeting on the Molecular Biology of Hepatitis B Viruses
  • Place of Presentation: Centennial Concert Hall, Yonsei University, Korea, Seoul
  • Year and Date: 2016-09-21
  • Int'l Joint Research
• [Presentation] Suppression of the hepatitis B virus (HBV) antigen expression in the liver prevents HBV-specific CD8 T cell exhaustion (2016)
  • 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: Centennial Concert Hall, Yonsei University, Korea, Seoul
  • Year and Date: 2016-09-21
  • Int'l Joint Research
• [Presentation] 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): 五十川正記, 河島圭吾, 田中靖人
  • Organizer: 第52回日本肝臓学会総会
  • Place of Presentation: ホテルニューオータニ幕張, 千葉,千葉
  • Year and Date: 2016-05-19
• [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,千葉
  • Year and Date: 2016-05-19
• [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, 新宿
  • Year and Date: 2016-04-21
• [Presentation] Endogenous antigen presentation by hepatocytes plays an essential role in the induction of HBV-specific CD8+ T cell responses (2016)
  • Author(s): Isogawa M, Murata Y, Kawashima K, Tanaka Y
  • Organizer: 4th Taiwan-Korea-Japan Research Symposium on Hepatitis B Virus
  • Place of Presentation: Academia Sinica, Taiwan, Taipei
  • Year and Date: 2016-04-09
• [Presentation] Novel 4'-modified nucleoside analogs exert antiviral replication against hepatitis B virus with drug resistance mutations (2016)
  • Author(s): Hayashi S, Takamatsu Y, Maeda K, Murakami S, Omagari K, Matsui T, Isogawa M, Watanabe T, Karino Y, Kohgo S, Mitsuya H, Tanaka Y
  • Organizer: 25th Conference of the Asian Pasific Association for the Study of the Liver (APASL2016)
  • Place of Presentation: International Convention Center Pamir, Tokyo, Japan
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] Host and viral determinants for differential hepatitis B virus clearance between genotypes (2016)
  • Author(s): Kawashima K, Isogawa M, Tsutsumi S, Murakami S, Saito S, Nakajima A, Tanaka Y. 25th Conference of the Asian Pasific Association for the Study of the Liver (APASL2016), 2016/2/
  • Organizer: 25th Conference of the Asian Pasific Association for the Study of the Liver (APASL2016)
  • Place of Presentation: International Convention Center Pamir, Tokyo, Japan
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] Clearance rate of hepatitis B virus differs between genotypes in association with CD8+ T cell activation in the liver. (2015)
  • Author(s): Isogawa M, Kawashima K, Tsutsumi S, Murakami S, Tanaka Y
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場、福岡
  • Year and Date: 2015-11-22
• [Presentation] Identification of a flavonoid derivative that directly acts on hepatitis B virus surface protein and inhibits viral entry. (2015)
  • Author(s): Tsukuda S, Watashi K, Hamada Y, Isogawa M, Iwamoto M, Suzuki R, Aizaki H, Kojima S, Sugiyama M, Saito A, Tanaka Y, Mizokami M, Wakita T
  • Organizer: 第63回日本ウイルス学会学術集会
  • Place of Presentation: 福岡国際会議場、福岡
  • Year and Date: 2015-11-22
• [Presentation] Endogenous antigen presentation by hepatocytes plays an essential role in the induction of HBV-specific CD8+ T cell responses (2015)
  • Author(s): Isogawa M, Murata Y, Kawashima K, Tanaka Y
  • Organizer: The 66th Annual Meeting of the American Association for the Study of Liver Diseases(AASLD2015)
  • Place of Presentation: Moscone West Convention Center, San Francisco, USA
  • Year and Date: 2015-11-13
  • Int'l Joint Research
• [Presentation] Hepatocellular carcinoma-associated core N51H mutation enhances infectivity of hepatitis B virus genotype F1b by facilitating dimerization of the core protein (2015)
  • Author(s): Hayashi S, Khan A, Ogawa K, Kawashima K, Simons B, Jones C, Homan C, McMahon B, Murakami S, Iijima S, Isogawa M, Watanabe T, Tanaka Y
  • Organizer: 2015 International Meeting on the Molecular Biology of Hepatitis B Viruses
  • Place of Presentation: Dolce Bad Nauheim, Germany
  • Year and Date: 2015-10-04
  • Int'l Joint Research
• [Presentation] Differential hepatitis B virus clearance between genotypes is correlated with HBV-specific CD8+T cell responses in the liver (2015)
  • Author(s): Kawashima K, Isogawa M, Tsutsumi S, Murakami S, Saito S, Nakajima A, Tanaka Y
  • Organizer: 2015 International Meeting on the Molecular Biology of Hepatitis B Viruses
  • Place of Presentation: Dolce Bad Nauheim, Germany
  • Year and Date: 2015-10-04
  • Int'l Joint Research
• [Presentation] Comparison of cytopathic and non-cytopathic antiviral effects of interferon alpha and lambda against hepatitis B virus infection. (2015)
  • Author(s): Tsutsumi S, Watanabe T, Kawashima K, Murakami S, Isogawa M, Tanaka Y
  • Organizer: 2015 International Meeting on the Molecular Biology of Hepatitis B Viruses
  • Place of Presentation: Dolce Bad Nauheim, Germany
  • Year and Date: 2015-10-04
  • Int'l Joint Research
• [Presentation] 新規エンテカビル耐性株の同定とその特徴 (2015)
  • Author(s): 林佐奈衣, 村上周子, 尾曲克己, 松居剛志, 飯尾悦子, 五十川正記, 渡邊綱正, 狩野吉康, 田中靖人
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: ホテル日航熊本、熊本県
  • Year and Date: 2015-05-21
• [Presentation] 肝細胞による内因性抗原提示と樹状細胞による外因性抗原提示がHBV特異的CD8＋T細胞応答に及ぼす相対的役割 (2015)
  • Author(s): 五十川正記, 村田泰洋, 田中靖人
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: ホテル日航熊本、熊本県
  • Year and Date: 2015-05-21
• [Presentation] 異なるHBV遺伝子型間で認められるHBV抗原遷延化率の違いと肝臓内CD8＋T細胞応答の相関性 (2015)
  • Author(s): 河島圭吾, 五十川正記, 松波加代子, 堤進, 村上周子, 渡邊綱正, 斉藤聡, 中島淳, 田中靖人
  • Organizer: 第51回日本肝臓学会総会
  • Place of Presentation: ホテル日航熊本、熊本県
  • Year and Date: 2015-05-21
• [Presentation] Check Point Inhibitors and Therapy for HBV Infection. (2015)
  • Author(s): Isogawa M.
  • Organizer: 17th International Conference on Emerging Infectious Diseases
  • Place of Presentation: Taipei (Taiwan)
  • Year and Date: 2015-01-25
• [Presentation] HBV 特異的 CD8+T 細胞の増殖と細胞傷害能は肝細胞による内因性抗原提示に依存する (2014)
  • Author(s): 五十川 正記、村田 泰洋、田中 靖人
  • Organizer: 第62回日本ウイルス学会学術集会
  • Place of Presentation: パシフィコ横浜会議センター（神奈川県・横浜市）
  • Year and Date: 2014-11-10 – 2014-11-12
• [Presentation] Endogenous Antigen Presentation By Hepatocytes Plays and Essential Role in the Induction of HBV-Specific CD8+ T cell responses. (2014)
  • Author(s): Isogawa M, Murata Y, Sheikh K, Tanaka Y, Chisari FV.
  • Organizer: 2014 International Meeting on Molecular Biology of Hepatitis B Viruses
  • Place of Presentation: Los Angeles (USA)
  • Year and Date: 2014-09-03 – 2014-09-06
• [Presentation] A VLP Based Therapeutic HBV Vaccine Designed to Inhibit Viral Spread. (2014)
  • Author(s): Whitacre D, Peterson D, Sureau C, Milich D, Isogawa M.
  • Organizer: International Meeting on Molecular Biology of Hepatitis B Viruses
  • Place of Presentation: Los Angeles (USA)
  • Year and Date: 2014-09-03 – 2014-09-06