Research about the key molecule to contribute for hepatitis C virus elimination from the aspect of liver host cell and immune cells

• Project/Area Number: 19590771
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Ehime University
• Principal Investigator: HIASA Yoichi Ehime University, 医学部附属病院, 講師 (70314961)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2007: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: C型肝炎ウイルス / インターフェロン / インターフェロン誘導遺伝子 / リバビリン末梢血リンパ球 / 内因性IFN-β / PKR / MxA / リバビリン / 末梢血リンパ球 / 複製モデル / 末梢血T細胞 / 2'5'-OAS

Research Abstract

C型肝炎ウイルス(HCV)は慢性持続感染し、インターフェロン(IFN)、リバビリン(RBV)がその治療に用いられている。本研究ではHCV排除に関わる宿主細胞因子を、培養肝細胞によるHCV複製系、および患者末梢血リンパ球を用いて、肝細胞、免疫細胞の両面から検討した。その結果、IFNによるHCV排除に、IFN誘導遺伝子(ISG)とりわけPKRが重要な因子であることが同定された。またRBVは肝細胞内因性IFN-β誘導作用を有し、IFNによって誘導されたISGをさらに増強し、この作用はRBVの臨床的治療効果に合致するものと考えられた。さらにRBVのような内因性IFN-β誘導能を持つ新たな抗HCV薬は、IFNとの併用により相乗的な抗HCV効果を発揮する可能性があり、今後のHCVに対する創薬のヒントとなると考えられた。

Research Products

• [Journal Article] Hepatitis C virus replication is inhibited by 22β-methoxyolean-12-ene -3β, 24(4β)-diol(ME3738) through enhancing IFN-β (2008)
  • Author(s): Hiasa Y, Kuzuhara H, Tokumoto Y(他6名, 1番目)
  • Journal Title: Hepatology 72巻 Pages: 867-872
  • Peer Reviewed
• [Journal Article] Neuropsychiatric dysfunction in patients with chronic hepatitis and liver cirrhosis (2008)
  • Author(s): Michitaka K, Tokumoto Y, Hiasa Y(他10名, 9番目)
  • Journal Title: Hepatology Research 38巻 Pages: 1069-1075
  • Peer Reviewed
• [Journal Article] Wilms' tumor 1 gene expression is increased in hepatocellular carcinoma and associated with poor prognosis (2008)
  • Author(s): Sera T, Hiasa Y, Mashiba T(他7名, 2番目)
  • Journal Title: European Journal of Cancer 44巻 Pages: 600-608
  • Peer Reviewed
• [Journal Article] Impaired dendritic cell functions because of depletion of natural killer cells disrupt antigen-specific immune responses in mice (2008)
  • Author(s): Yoshida O, Akbar F, Hiasa Y(他4名, 6番目)
  • Journal Title: Clinical Experimental Immunology 152巻 Pages: 174-181
  • Peer Reviewed
• [Journal Article] Liver/spleen volume ratio as a predictor of prognosis in primary biliary cirrhosis (2008)
  • Author(s): Murata Y, Abe M, Hiasa Y(他7名, 3番目)
  • Journal Title: Journal of Gastroenterology 43巻 Pages: 632-636
  • Peer Reviewed
• [Journal Article] Efficacy of splenectomy for hypersplenic patients with advanced hepatocellular carcinoma (2008)
  • Author(s): Hirooka M, Ishida K, Hiasa Y(他5名, 6番目)
  • Journal Title: Hepatology Research 38巻 Pages: 1172-1177
  • Peer Reviewed
• [Journal Article] Characteristic endoscopic features of portal hypertensive enteropathy (2008)
  • Author(s): Higaki N, Matsui H, Hiasa Y(他5名, 6番目)
  • Journal Title: Journal of Gastroenterology 43巻 Pages: 327-331
  • Peer Reviewed
• [Journal Article] Protective role of interleukin-10-producing regulatory dendritic cells against murine autoimmune dendritic cells against murine autoimmune (2008)
  • Author(s): Torisu M, Murakami H, Akbar F, Hiasa Y(他4名, 5番目)
  • Journal Title: Journal of Gastroenterology 43巻 Pages: 100-107
  • Peer Reviewed
• [Journal Article] Mutational analysis of predicted intracellular loop domains of human motilin receptor (2008)
  • Author(s): Tokunaga H, Matsuura B, Hiasa Y(他5名, 7番目)
  • Journal Title: American Journal of Physiology Gastrointestinal and Liver Physiology 294巻 Pages: 460-466
  • Peer Reviewed
• [Journal Article] Hepatitis C virus replication is inhibited by 22β-methoxyolean-12-ene-3β, 24(4β)-diol (ME3738) through enhancing IFN-β (2008)
  • Author(s): Hiasa Y, Kuzuhara H, Tokumoto Y, (他6名, 1番目)
  • Journal Title: Hepatology 72 Pages: 867-872
  • Peer Reviewed
• [Journal Article] Impaired dendritic cell functions because of depletion of natural killer cells disrupt antigen-specific immune responses in mice (2008)
  • Author(s): Yoshida O, Akbar F, Hiasa Y, (他4名, 6番目)
  • Journal Title: Clinical Experimental Immunology 152 Pages: 174-181
  • Peer Reviewed
• [Journal Article] Mutational analysis of predicted intracellular loop domains of human motilin receptor (2008)
  • Author(s): Tokunaga H, Matsuura B, Hiasa Y, (他5名, 7番目)
  • Journal Title: American Journal of Physiology Gastrointestinal and Liver Physiology 294 Pages: 460-466
  • Peer Reviewed
• [Journal Article] Wilms' tumour 1 gene expression is increased in hepatocellular carcinoma and associated with poor prognosis (2008)
  • Author(s): Sera T, Hiasa Y, Mashiba T, Tokumoto Y, Hirooka M, et. al.
  • Journal Title: European Journal of Cancer 44 Pages: 600-608
  • Peer Reviewed
• [Journal Article] Engineering immune therapy against hepatitis B virus (2007)
  • Author(s): Akbar F, Yoshida O, Hiasa Y(他2名, 4番目)
  • Journal Title: Hepatology Research 37巻 Pages: 351-356
  • Peer Reviewed
• [Journal Article] Hepatitis C virus expression and interferon antiviral action is dependent on PKR expression (2007)
  • Author(s): Tokumoto Y, Hiasa Y, Horiike N(他4名, 2番目)
  • Journal Title: Journal of Medical Virology 79巻 Pages: 1120-1127
  • Peer Reviewed
• [Journal Article] Characteristics of lamivudine-resistant hepatitis B virus(HBV) strains with and without breakthrough hepatitis in patients with chronic hepatitis B evaluated by serial HBV full-genome sequences (2007)
  • Author(s): Horiike N, Duong TN, Hiasa Y(他5名, 5番目)
  • Journal Title: Journal of Medical Virology 79巻 Pages: 911-918
  • Peer Reviewed
• [Journal Article] Compartmentalization of hepatitis C virus(HCV) during HCV/HIV coinfection (2007)
  • Author(s): Blackard JT, Hiasa Y, Smeaton L(他4名, 2番目)
  • Journal Title: Journal of Infectious Disease 195巻 Pages: 1765-1773
  • Peer Reviewed
• [Journal Article] Impaired dendritic cell function resulting from chronic undernutrition disrupts the antigen-specific immune response in mice (2007)
  • Author(s): Niiya T, Akbar SMF, Hiasa Y(他6名, 8番目)
  • Journal Title: Journal of Nutrition 137巻 Pages: 671-675
  • Peer Reviewed
• [Journal Article] Identification of CTL epitopes in hepatitis C virus by a genome-wide computational scanning and a rational design of peptide vaccine (2007)
  • Author(s): Mashiba T, Udaka K, Hiasa Y(他7名, 4番目)
  • Journal Title: Immunogenetics 59巻 Pages: 197-209
  • Peer Reviewed
• [Journal Article] Induction of anti-HBs in HB vaccine nonresponders in vivo by hepatitis B surface antigen-pulsed blood dendritic cells (2007)
  • Author(s): Akbar SMF, Furukawa S, Hiasa Y(他3名, 4番目)
  • Journal Title: Journal of Hepatology 47巻 Pages: 60-66
  • Peer Reviewed
• [Journal Article] Percutaneous ultrasound-guided radiofrequency ablation of hepatocellular carcinoma with artificially induced pleural effusion and ascites (2007)
  • Author(s): Uehara T, Hirooka M, Hiasa Y(他5名, 3番目)
  • Journal Title: Journal of Gastroenterology 42巻 Pages: 306-311
  • Peer Reviewed
• [Journal Article] Recurrence of autoimmune hepatitis after liver transplantation without elevation of alanine aminotransferase (2007)
  • Author(s): Yao H, Michitaka K, Hiasa Y(他6名, 7番目)
  • Journal Title: World Journal of Gastroenterology 13巻 Pages: 1618-1621
  • Peer Reviewed
• [Journal Article] Diabetes mellitus reduces the therapeutic effectiveness of interferon-alpha2b plus ribavirin therapy in patients with chronic hepatitis C (2007)
  • Author(s): Konishi I, Horiike N, Hiasa Y(他8名, 3番目)
  • Journal Title: Hepatology Research 37巻 Pages: 331-336
  • Peer Reviewed
• [Journal Article] Characteristics of geographic distributions and route of infection for hepatitis B virus genotype D in Ehime area in western Japan (2007)
  • Author(s): Matsuura K, Michitaka K, Hiasa Y(他6名, 7番目)
  • Journal Title: Hepatology Research 37巻 Pages: 255-262
  • Peer Reviewed
• [Journal Article] Prevalence of hepatitis E virus among wild boar in the Ehime area of western Japan (2007)
  • Author(s): Michitaka K, Takahashi K, Hiasa Y(他6名, 5番目)
  • Journal Title: Hepatology Research 37巻 Pages: 214-220
  • Peer Reviewed
• [Journal Article] Significance of laparoscopic splenectomy in patients with hypersplenism (2007)
  • Author(s): Watanabe Y, Horiuchi A, Hiasa Y(他5名, 7番目)
  • Journal Title: World Journal of Surgery 31巻 Pages: 549-555
  • Peer Reviewed
• [Journal Article] Heterogeneity of hepatitis B virus genotype D in Japan (2007)
  • Author(s): Michitaka K, Horiike N, Hiasa Y(他8名, 10番目)
  • Journal Title: Intervirology 50巻 Pages: 150-155
  • Peer Reviewed
• [Journal Article] Dietary habits and nutrient intake in non-alcoholic steatohepatitis (2007)
  • Author(s): Toshimitsu K, Matsuura B, Hiasa Y(他6名, 6番目)
  • Journal Title: Nutrition 23巻 Pages: 46-52
  • Peer Reviewed
• [Journal Article] Hepatitis C virus expression and interferon antiviral action is dependent on PKR expression (2007)
  • Author(s): Tokumoto Y, Hiasa Y, Horiike N, Michitaka K, et. al.
  • Journal Title: Journal of Medical Virology 79 Pages: 1120-1127
  • Peer Reviewed
• [Journal Article] Compartmentalization of hepatitis C virus (HCV) during HCV/HIV coinfection (2007)
  • Author(s): Blackard JT, Hiasa Y, Smeaton L, Jamieson DJ, et. al.
  • Journal Title: Journal of Infectious Disease 195 Pages: 1765-1773
  • Peer Reviewed
• [Presentation] The enhancement of autocrine interferon-beta and the decrease of SOCS-3 by ME3738 would contribute the synergistic anti-HCV effects combined with interferon-alpha (2008)
  • Author(s): Hiasa Y, Tokumoto Y, Konishi I(他2名, 1番目)
  • Organizer: 第59回米国肝臓学会
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2008-11-04
• [Presentation] The enhancement of autocrine interferon-beta and the decrease of SOCS-3 by ME3738 would contribute the synergistic anti-HCV effects combined with interferon-alpha (2008)
  • Author(s): Hiasa Y, Tokumoto Y, Konishi I, (他2名, 1番目).
  • Organizer: The 59^<th> Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2008-11-04
• [Presentation] Ribavirin upregulates autocrine interferon-β and interferon stimulated genes in the early phase of the combination treatment with interferon-α (2008)
  • Author(s): Tokumoto Y, Hiasa Y, Konishi I(他4名, 2番目)
  • Organizer: 第59回米国肝臓学会
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2008-11-03
• [Presentation] HepG2細胞におけるME3738による内因性IFN-βの増加とその抗HCV 効果 (2008)
  • Author(s): 日浅陽一、徳本良雄、小西一郎(他2名, 1番目)
  • Organizer: 第50回日本消化器病学会大会
  • Place of Presentation: 東京
  • Year and Date: 2008-10-01
• [Presentation] リバビリンによるインターフェロン誘導遺伝子の修飾と治療効果への役割 (2008)
  • Author(s): 徳本良雄、日浅陽一、恩地森一
  • Organizer: 第44回日本肝臓学会総会
  • Place of Presentation: 松山
  • Year and Date: 2008-06-05
• [Presentation] 高齢者(65歳以上)のC型慢性肝炎患者における抗ウイルス治療効果 (2007)
  • Author(s): 日浅陽一、小西一郎、世良俊樹(他4名, 1番目)
  • Organizer: 第37回日本肝臓学会西部会
  • Place of Presentation: 長崎
  • Year and Date: 2007-12-08
• [Presentation] ME3738 inhibits hepatitis C virus replication by enhancing interferon-beta (2007)
  • Author(s): Hiasa Y, Tokumoto Y, Konishi I(他4名, 1番目)
  • Organizer: 第58回米国肝臓学会
  • Place of Presentation: Boston, MA, USA
  • Year and Date: 2007-11-06
• [Presentation] ME3738 inhibits hepatitis C virus replication by enhancing interferon-beta (2007)
  • Author(s): Hiasa Y, Tokumoto Y, Konishi I, Matsuura B, et. al.
  • Organizer: The 58^<th> Annual Meeting of the American Association for the Study of Liver Diseases
  • Place of Presentation: Boston,MA,USA
  • Year and Date: 2007-11-06
• [Presentation] ME3738とインターフェロン併用による抗HCV効果の基礎的検討 (2007)
  • Author(s): 日浅陽一、徳本良雄、小西一郎(他5名, 1番目)
  • Organizer: 第11回日本肝臓学会大会
  • Place of Presentation: 神戸
  • Year and Date: 2007-10-18
• [Presentation] C型肝炎に対する免疫療法 (2007)
  • Author(s): 日浅陽一、眞柴寿枝、恩地森一
  • Organizer: 第43回日本肝臓学会総会
  • Place of Presentation: 東京
  • Year and Date: 2007-05-31
• [Book] インターフェロンを中心に合併症のある症例自己免疫性肝疾患. そこが知りたいC型肝炎のベスト治療 (2009)
  • Author(s): 日浅陽一、恩地森一
  • Publisher: 医学書院
• [Book] HBc抗原特異的細胞傷害性T細胞を誘導しうるHBc抗原ワクチン療法の開発. 第10回学術集会記録集 (2008)
  • Author(s): 日浅陽一
  • Publisher: Liver Forum in Kyoto
• [Book] 合併症のある症例 自己免疫性肝疾患そこが知りたい C型肝炎のベスト治療 インターフェロンを中心に (2008)
  • Author(s): 日浅陽一, 恩地森一(分担執筆)
  • Publisher: 医学書院