The search of the drug for the acute severe HBV hepatitis using animal model

• Project/Area Number: 15K09003
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Institute of Physical and Chemical Research (2016-2017); Hiroshima University (2015)
• Principal Investigator: Hiraga Nobuhiko 国立研究開発法人理化学研究所, 統合生命医科学研究センター, 客員研究員 (50625978)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: B型肝炎ウイルス / マウス / HBV / ｃｃｃDNA

Outline of Final Research Achievements

The treatment for acute infection of hepatitis B virus is to control the host immune response and the exclusion of intracellular cccDNA in HBV-infected hepatocytes. The covalently closed circular DNA (cccDNA) forms a stable minichromosome in the nuclei of HBV infected hepatocytes in spite of acute HBV. We established an animal model of fulminant hepatitis caused by HBV infection using human hepatocyte chimeric TK-NOG mice transplanted human peripheral blood monocytes (PBMCs). We found that 1) interferon and nucleotide/nucleoside analogues, which are the main drugs for chronic HBV, are useful for acute HBV. 2) Antibody to HBsAg (anti-HBs) immunoglobulin (HBIG), which can inhibit HBV entry, became hepatitis B surface antigen negative. 3) CTLA4Ig was shown to be effective in suppressing hepatitis. Our results indicate that existing drugs might be useful for treatment for acute HBV.

Research Products

• [Journal Article] Persistent loss of HBV markers in serum without cellular immunity by combination of PEG-IFN plus ETV therapy in humanized mice (2017)
  • Author(s): Uchida T, Imamura M, Hayes CN, Hiraga N, Kan H, Tsuge M, Abe-Chayama H, Zhang Y, Makokha GN, Aikata H, Miki D, Ochi H, Ishida Y, Tateno C, Chayama K
  • Journal Title: Antimicrob Agents Chemother Volume: 61 Issue: 9
  • DOI: 10.1128/aac.00725-17
  • Peer Reviewed / Open Access
• [Journal Article] Antiviral effects of anti-HBs immunoglobulin and vaccine on HBs antigen seroclearance for chronic hepatitis B infection. (2016)
  • Author(s): Tsuge M, Hiraga N, Uchida T, Kan H, Miyaki E, Masaki K, Ono A, Nakahara T, Abe-Chayama H, Zhang Y, Naswa MG, Kawaoka T, Miki D, Imamura M, Kawakami Y, Aikata H, Ochi H, Hayes CN, Chayama K.
  • Journal Title: Journal of Gastroenterology Volume: In press Issue: 11 Pages: 1073-1080
  • DOI: 10.1007/s00535-016-1189-x
  • Peer Reviewed / Open Access
• [Journal Article] Human Cytotoxic T Lymphocyte-Mediated Acute Liver Failure and Rescue by Immunoglobulin in Human Hepatocyte Transplant TK-NOG Mice. (2015)
  • Author(s): Uchida T., Hiraga N., Imamura M., Tsuge M., Abe H., Hayes C.N., Aikata H., Ishida Y., Tateno C., Yoshizato K., Ohdan H., Murakami K. and Chayama K.
  • Journal Title: Journal of Virology Volume: 89 Issue: 19 Pages: 10087-96
  • DOI: 10.1128/jvi.01126-15
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Human cytotoxic T lymphocyte mediated acute liver failure and rescue by immunoglobulin in human hepatocyte transplanted TKNOG mice (2016)
  • Author(s): Uchida T, Hiraga N, Imamura M, Yoshimi S, Kan H, Miyaki E, Tsuge M, Abe H, Hayes CN, Aikata H, Ishida Y, Tateno C, Ellis JD, Chayama
  • Organizer: Asian Pacific Association for the Study of the Liver.
  • Place of Presentation: 東京（国際館パミール）
  • Year and Date: 2016-02-20
  • Int'l Joint Research
• [Presentation] Human cytotoxic T lymphocyte mediated acute liver failure and rescue by immunoglobulin in human hepatocyte transplanted TKNOG mice (2015)
  • Author(s): Uchida T, Hiraga N, Imamura M, Yoshimi S, Kan H, Miyaki E, Tsuge M, Abe H, Hayes CN, Aikata H, Ishida Y, Tateno C, Ellis JD, Chayama K.
  • Organizer: 2015 Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: サンフランシスコ
  • Year and Date: 2015-11-13
  • Int'l Joint Research
• [Presentation] ヒト肝細胞キメラマウスを用いた急性B型肝炎モデルの構築 (2015)
  • Author(s): 平賀伸彦，今村道雄，茶山一彰
  • Organizer: 日本肝臓学会 第19回大会
  • Place of Presentation: グランドプリンスホテル新高輪
  • Year and Date: 2015-10-08