Basic study for HBV clearance using cytokines induced by nucleotide analogues

• Project/Area Number: 17K09448
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: International University of Health and Welfare (2018-2019); National Center for Global Health and Medicine (2017)
• Principal Investigator: MURATA KAAUMOTO 国際医療福祉大学, 医学部, 教授 (40345971)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2019: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: B型肝炎 / サイトカイン / 免疫賦活 / 核酸アナログ製剤 / B型慢性肝炎 / mTOR / IFN-λ3

Outline of Final Research Achievements

We found that adefovir (ADV) or tenofovir (TDF) ①induced IFN-lambda3, and ②inhibited interleukin (IL)-10 and induced IL-12, all of which immunologically lead toward hepatitis B virus (HBV) elimination. Combination of ADV or TDF with IFN-alpha showed additional and synergistic effects on those cytokines production. A mechanistic analysis revealed that ADV or TDF inhibited signals that enhanced in tumor cells. We also found several powerful inducers by screening.

Academic Significance and Societal Importance of the Research Achievements

今回の研究にて、現在使用されている核酸アナログ製剤のうちADV・TDFには、B型肝炎ウイルス(HBV)排除に有利な免疫状態を誘導するという追加効果があることが判明した。さらに、強力にIFN-lambda3を誘導する候補薬剤も見出した。また、ADV・TDFは肝発癌抑制効果があることも見出したことから、これらを利用したHBV排除、発がん抑制に関する新たな治療戦略が構築されると考えられる。

Research Products

• [Journal Article] IFN-λ3 as a host immune response in acute hepatitis E virus infection (2020)
  • Author(s): Murata K, Kang JH, Nagashima S, Matsui T, Karino Y, Yamamoto Y, Atarashi T, Oohara M, Uebayashi M, Sakata H, Matsubayashi K, Takahashi K, Arai M, Mishiro S, Sugiyama M, Mizokami M, Okamoto H.
  • Journal Title: Cytokine Volume: 125 Pages: 154816-154816
  • DOI: 10.1016/j.cyto.2019.154816
  • Peer Reviewed
• [Journal Article] Anti‐viral effects of interferon‐λ3 on hepatitis B virus infection in cell culture (2020)
  • Author(s): Yamada Norie、Murayama Asako、Shiina Masaaki、Aly Hussein Hassan、Iwamoto Masashi、Tsukuda Senko、Watashi Koichi、Tanaka Tomohisa、Moriishi Kohji、Nishitsuji Hironori、Sugiyama Masaya、Mizokami Masashi、Shimotohno Kunitada、Muramatsu Masamichi、Murata Kazumoto、Kato Takanobu
  • Journal Title: Hepatology Research Volume: 50 Issue: 3 Pages: 283-291
  • DOI: 10.1111/hepr.13449
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] .Association of serum IFN-λ3 levels with hepatocarcinogenesis in chronic hepatitis C patients treated with direct-acting antiviral agents. (2019)
  • Author(s): Emi Inoue-Shinomiya, Miyako Murakawa, Yasuhiro Asahina, Mina Nakagawa, Jun Tsuchiya, Ayako Sato, Tomoyuki Tsunoda, Masato Miyoshi, Sayuri Nitta, Fukiko Kawai-Kitahata, Yasuhiro Itsui, Seishin Azuma, Sei Kakinuma, Kazumoto Murata, Masashi Mizokami, Mamoru Watanabe.
  • Journal Title: Hepatology Research Volume: 印刷中 Issue: 5 Pages: 500-511
  • DOI: 10.1111/hepr.13307
  • Peer Reviewed / Open Access
• [Journal Article] POGLUT1, the putative effector gene driven by rs2293370 in primary biliary cholangitis susceptibility locus chromosome 3q13.33 (2019)
  • Author(s): Hitomi, Y. Ueno, K. Kawai, Y. Nishida, N. , Umemura, T. et al
  • Journal Title: Sci Rep Volume: 9 Issue: 1 Pages: 102-102
  • DOI: 10.1038/s41598-018-36490-1
  • NAID: 120006715480
  • Peer Reviewed / Open Access
• [Journal Article] Immunomodulatory mechanism of acyclic nucleoside phosphates in treatment of hepatitis B virus infection. (2019)
  • Author(s): Murata K, Tsukuda S, Suizu F, Kimura A, Sugiyama M, Watashi K, Noguchi M, Mizokami M.
  • Journal Title: Hepatology Volume: 71 Issue: 5 Pages: 1533-1545
  • DOI: 10.1002/hep.30956
  • Peer Reviewed
• [Journal Article] Combinational use of (2018)
  • Author(s): Matsumoto A, Nishiguchi S, Enomoto H, Kang JH, Tanaka Y, Shinkai N, Kurosaki M, Enomoto M, Kanda T, Yokosuka O, Yatsuhashi H, Nagaoka S, Okuse C, Kagawa T, Mine T, Takaguchi K, Saito S, Hino K, Ikeda F, Sakisaka S, Morihara D, Miyase S, Tsuge M, Chayama K, Hiramatsu N, Suzuki Y, Murata K, Tanaka E
  • Journal Title: J Gastroenterol Volume: 53 Issue: 2 Pages: 247-257
  • DOI: 10.1007/s00535-017-1360-z
  • Peer Reviewed / Open Access
• [Journal Article] Association of des-gamma-carboxy prothrombin production and Sonazoid-enhanced ultrasound findings in hepatocellular carcinoma of different histologic grades (2018)
  • Author(s): Murata K, Saito A, Katagiri S, Ariizumi S, Nakano M, Yamamoto M
  • Journal Title: J Med Ultrason Volume: 45 Issue: 2 Pages: 223-229
  • DOI: 10.1007/s10396-017-0816-3
  • Peer Reviewed
• [Journal Article] 核酸アナログ製剤によるIFN-lambda誘導とそれを標的としたB型肝炎治療薬の探索 (2018)
  • Author(s): 村田一素、前仲勝実、溝上雅史
  • Journal Title: Mebio Volume: 1 Pages: 80-87
• [Journal Article] Key HLA-DRB1-DQB1 haplotypes and role of the BTNL2 gene for response to a hepatitis B vaccine. (2018)
  • Author(s): Nishida N, Sugiyama M, Sawai H, Nishina S, Sakai A, Ohashi J, Khor SS, Kakisaka K, Tsuchiura T, Hino K, Sumazaki R, Takikawa Y, Murata K, Kanda T, Yokosuka O, Tokunaga K, Mizokami M
  • Journal Title: Hepatology Volume: 印刷中 Issue: 3 Pages: 848-858
  • DOI: 10.1002/hep.29876
  • Peer Reviewed / Open Access
• [Journal Article] Genome-wide association study identified new susceptible genetic variants in HLA class I region for hepatitis B virus-related hepatocellular carcinoma (2018)
  • Author(s): awai H, Nishida N, Sugiyama M, Murata K, Hino K, Nishina S, Matsumoto A, Tanaka E, Sakamoto N, Ogawa K, Yamamoto K, Tamori A, Yokosuka O, Kanda T, Sakaida I, Itoh Y, Eguchi Y, Oeda S, Mochida S, Yuen MF, Seto WK, Poovorawan Y, Posuwan N, Mizokami M, Tokunaga K
  • Journal Title: Ｓｃｉ Ｒｅｐ Volume: 8 Issue: 1 Pages: 7958-7958
  • DOI: 10.1038/s41598-018-26217-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 核酸アナログ製剤によるIFN-λ誘導とそれを標的としたB型肝炎治療薬の探索 (2018)
  • Author(s): 村田一素、前仲勝実、溝上雅史
  • Journal Title: Mebio Volume: 1 Pages: 80-87
• [Journal Article] アデフォビル、テノフォビルによるIFN-λ3誘導とその意義 (2017)
  • Author(s): 村田一素、杉山真也
  • Journal Title: 医学のあゆみ Volume: 262 Pages: 1327-1330
• [Journal Article] Induction of IFN-lambda3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection (2016)
  • Author(s): Murata, K. Asano, M. Matsumoto, A. Sugiyama, M. Nishida, N. Tanaka, E. Inoue, T. Sakamoto, M. Enomoto, N. Shirasaki, T. Honda, M. Kaneko, S. Gatanaga, H. Oka, S. Kawamura, Y. I. Dohi, T. Shuno, Y. Yano, H. Mizokami, M.
  • Journal Title: Gut Volume: - Issue: 2 Pages: 362-371
  • DOI: 10.1136/gutjnl-2016-312653
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] 核酸アナログ製剤による免疫賦活サイトカイン誘導とそのIFN-alpha 併用効果 (2019)
  • Author(s): 村田一素、杉山真也、溝上雅史
  • Organizer: 第105回日本消化器病学会総会
• [Presentation] Novel immune-modulatory and anti-tumor effect of acyclic nucleoside phosphonates (2019)
  • Author(s): Kazumoto Murata, Masaya Sugiyama, Masashi Mizokami
  • Organizer: 第55回日本肝臓学会総会
• [Presentation] Adefovir or tenofovir affects lipopolysaccharide-mediated cytokine production in CD14+monocytes though mammalian target of rapamycin pathway (2019)
  • Author(s): Kazumoto Murata, Masaya Sugiyama, Masashi Mizokami
  • Organizer: International HBV meeting
  • Int'l Joint Research
• [Presentation] Clinical application of a novel additional pharmacological effect to induce IFN-lambda3 by adefovir or tenofovir (2018)
  • Author(s): Murata K
  • Organizer: Taiwan-Japan-Korea HBV Research meeting
  • Int'l Joint Research
• [Presentation] 新規治療薬探索のためのアデフォビル・テノフォビルによるIFN-λ3誘導機序の解明 (2018)
  • Author(s): 村田一素、杉山真也、溝上雅史
  • Organizer: 日本肝臓学会総会
• [Presentation] Adefovir or tenofovir reciprocally augment pro-inflammatory cytokines in LPS-stimulated PBMC by inhibiting IL-10 production in CD14+monocytes (2018)
  • Author(s): Murata K, Sugiyama M, Mizokami M
  • Organizer: AASLD
  • Int'l Joint Research
• [Presentation] IFN-lambdaを標的とした新規B型肝炎治療薬の探索 (2017)
  • Author(s): 村田一素、前仲勝実、溝上雅史
  • Organizer: 第53回日本肝臓学会総会
• [Presentation] Induction of IFN-λ3 by ADV or TDF as a new potential target for HBV infection (2017)
  • Author(s): Murata K, Sugiyama M, Otsuguro S, Maenaka K, Mizokami M
  • Organizer: International HBV meeting
  • Int'l Joint Research
• [Presentation] TDF/Peg-IFN併用療法におけるHBsAg量低下の初期反応 (2017)
  • Author(s): 松本晶博、村田一素、田中榮司
  • Organizer: 第21回日本肝臓学会大会