ＨＣＶ培養系を用いたＩ型・ＩＩＩ型インターフェロン不応性機構の解析

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24590960
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: 大岡 真也 東京医科歯科大学, 医歯(薬)学総合研究科, 特任准教授 (90361691)
• Co-Investigator(Kenkyū-buntansha): 朝比奈 靖浩 東京医科歯科大学, 医歯(薬)学総合研究科, 寄附講座教授 (00422692) ; 渡辺 守 東京医科歯科大学, 医歯(薬)学総合研究科, 教授 (10175127)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: HCV / Cardif / IFNλ

Outline of Annual Research Achievements

申請者らはC型慢性肝炎に対するPEG-IFN、Ribavirin治療効果を予測するゲノムワイド研究から、IL28B領域に強い連鎖不均衡を伴い存在するminor alleleが、非常に高い確率で難治と関連することを報告したが、この領域はType-III IFN (IFN-λ)の産生locusであり、ウイルス感染、およびIFN-αにより二次的に発現誘導される。この領域の遺伝子多型、即ちmajor (著効例)およびminor(難治例)alleleの機能を明らかとするために、IL28Bの転写調節能を検討した。その結果、IL28Bのpromoter活性はpoly I:C刺激およびRIG-I/IPS-1自然免疫系分子の刺激により10倍以上の上昇を認めたが、IL28B minor由来のpromoter活性の上昇はIL28B major由来のpromoter活性の上昇に比し有意に低かった。さらに、C型慢性肝炎患者の末梢血単核球を用いた検討では、難治例においてIL28B遺伝子発現が有意に低下していたことから、IL28B minor alleleに起因する難治機序にはIL28B promoter活性の低下がその本質に近い要因と考えられた。

Research Products

• [Journal Article] Impaired induction of IL28B and expression of IFNλ4 associated with non-response to interferon-based therapy in chronic hepatitis C. (2015)
  • Author(s): Murakawa M*, Asahina Y*, Nakagawa M, Sakamoto N, Nitta S, Kusano-Kitazume A, Watanabe T, Kawai-Kitahata F, Otani S, Taniguchi M, Goto F, Nishimura-Sakurai Y, Itsui Y, Azuma S, Kakinuma S, Watanabe M.
  • Journal Title: J Gastroenterol Hepatol Volume: - Pages: -
  • DOI: 10.1111/jgh.12902
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Serum granulysin levels as a predictor of serious telaprevir-induced dermatological reactions. (2015)
  • Author(s): Suda G, Yamamoto Y, Nagasaka A, Furuya K, Kudo M, Yoshimichi C, Tsukuda Y, Tsunematsu S, Sato F, Terasita K, Nakai M, Horimoto H, Sho T, Natsuizka M, Ogawa K, Ohnishi S, Chuma M, Fujita Y, Abe R, Taniguchi M, Nakagawa M, Asahina Y, Sakamoto N.
  • Journal Title: Hepatol Res Volume: - Pages: -
  • DOI: 10.1111/hepr.12421
  • Peer Reviewed
• [Journal Article] Hepatocellular carcinoma risk assessment using gadoxetic acid-enhanced hepatocyte phase magnetic resonance imaging. (2015)
  • Author(s): Komatsu N, Motosugi U, Maekawa S, Shindo K, Sakamoto M, Sato M, Tatsumi A, Miura M, Amemiya F, Nakayama Y, Inoue T, Fukasawa M, Uetake T, Ohtaka M, Sato T, Asahina Y, Kurosaki M, Izumi N, Ichikawa T, Araki T, Enomoto N.
  • Journal Title: Hepatol Res Volume: - Pages: -
  • DOI: 10.1111/hepr.12309
  • Peer Reviewed
• [Journal Article] Changes in plasma vascular endothelial growth factor at 8 weeks after sorafenib administration as predictors of survival for advanced hepatocellular carcinoma. (2014)
  • Author(s): Tsuchiya K*, Asahina Y*, Matsuda S, Muraoak M, Nakata T, Suzuki Y, Tamaki N, Yasui Y, Suzuki S, Hosokawa T, Nishimura T, Ueda K, Kuzuya T, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Enomoto N, Izumi N.
  • Journal Title: Cancer Volume: 20 Pages: 229-273
  • DOI: 10.1002/cncr.28384
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Risk factors for exceeding the Milan criteria after successful radiofrequency ablation in patients with early stage hepatocellular carcinoma. (2014)
  • Author(s): Tsuchiya K, Asahina Y, Tamaki N, Yasui Y, Hosokawa T, Ueda K, Nakanishi H, Itakura J, Kurosaki M, Enomoto N, Izumi N.
  • Journal Title: Liver Transpl Volume: 20 Pages: 291-297
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Reduced organic anion transporter expression is a risk factor for hepatocellular carcinoma in chronic hepatitis C patients: A propensity score matching study. (2014)
  • Author(s): Yasui Y, Kudo A, Kurosaki M, Matsuda S, Muraoka M, Tamak Ni, Suzuki S, Hosokawa T, Ueda K, Matsunaga K, Nakanishi H, Tsuchiya K, Itakura J, Takahashi Y, Tanaka S, Asahina Y, Enomoto N, Arii S, Izumi N.
  • Journal Title: Oncology Volume: 86 Pages: 53-62
  • DOI: 10.1159/000356643
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] New Susceptibility and Resistance HLA-DP Alleles to HBV-Related Diseases Identified by a Trans-Ethnic Association Study in Asia. (2014)
  • Author(s): Nishida N, Sawai H, Asahina Y, Mizokami M, et al.
  • Journal Title: PLoS One Volume: - Pages: -
  • DOI: 10.1371/journal.pone.0086449
  • Peer Reviewed
• [Journal Article] Impaired brain activity in cirrhotic patients with minimal hepatic encephalopathy: evaluation by near infrared spectroscopy. (2014)
  • Author(s): Nakanishi H, Kurosaki M, Nakanishi K, Tsuchiya K, Noda T, Tamaki N, Yasui Y, Hosokawa T, Ueda K, Itakura J, Anami K, Asahina Y, Enomoto N, Higuchi T, Izumi N.
  • Journal Title: Hepatol Res Volume: 44 Pages: 319-326
  • DOI: 10.1111/hepr.12127
  • Peer Reviewed
• [Journal Article] Prospective comparison of real-time tissue elastography and serum fibrosis markers for the estimation of liver fibrosis in chronic hepatitis C patients. (2014)
  • Author(s): Tamaki N, Kurosaki M, Matsuda S, Nakata T, Muraoka M, Suzuki Y, Yasui Y, Suzuki S, Hosokawa T, Nishimura T, Ueda K, Tsuchiya K, Nakanishi H, Itakura J, Takahashi Y, Matsunaga K, Taki K, Asahina Y, Izumi N.
  • Journal Title: Hepatol Res Volume: 44 Pages: 720-727
  • DOI: 10.1111/hepr.12179.
  • Peer Reviewed
• [Journal Article] JSH guidelines for the management of hepatitis B virus infection. (2014)
  • Author(s): Asahina Y, HayashinN, Hiramatsu N, Izumi N, Koike K, Kumada H, Kurosaki M, Oketani M, Suzuki F, Takikawa H, Tanaka A, Tanaka E, Tanaka Y, Tsubouchi H, Yotsuyanagi H.
  • Journal Title: Hepatol Res Volume: 44 Pages: 1-58
  • DOI: 10.1111/hepr.12269
  • Peer Reviewed
• [Journal Article] JSH guidelines for the management of hepatitis C virus infection: a 2014 update for genotype 1. (2014)
  • Author(s): Asahina Y, HayashinN, Hiramatsu N, Izumi N, Koike K, Kumada H, Kurosaki M, Oketani M, Suzuki F, Takikawa H, Tanaka A, Tanaka E, Tanaka Y, Tsubouchi H, Yotsuyanagi H.
  • Journal Title: Hepatol Res Volume: 44 Pages: 59-70
  • DOI: 10.1111/hepr.12272
  • Peer Reviewed
• [Presentation] Gene Alterations in TERT promoter, CTNNB1, and TP53 are closely associated with development and prognosis of hepatocellular carcinoma: comprehensive analyses by next generation sequencing technology. (2015)
  • Author(s): Asahina Y, Kawai-Kitahata F, Kaneko S, Nagata H, Goto F, Otani S, Taniguchi M, Murakawa M, Nitta S, Watanabe T, Tasaka-Fujita M, Itsui Y, Nakagawa M, Kakinuma S, Tanaka S, Tanabe M, Enomoto N, Watanabe M.
  • Organizer: he 50th annual meeting of the European association for the study of the liver (EASL The International Liver Congress 2015)
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2015-04-23
• [Presentation] Gene alterations in β-catenin and p53/ cell cycle control pathway are closely associated with development and prognosis of hepatocellular carcinoma: Comprehensive analyses by next generation sequencing technology. (2014)
  • Author(s): Kawai-Kitahata F, Asahina Y, Kaneko S, Nagata H, Goto F, Otani S, Taniguchi M, Murakawa M, Nitta S, Watanabe T, Tasaka-Fujita M, Itsui Y, Nakagawa M, Kakinuma S, Enomoto N, Watanabe M.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2014)
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Matrix Metalloproteinase-14 regulates the maturation of fetal hepatic stem/progenitor cells in mice. (2014)
  • Author(s): Otani S, Kakinuma S, Kamiya A, Goto F, Kaneko S, Azuma S, Asahina Y, Watanabe M.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2014)v
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Impact of host and therapeutic factors and resistant associated variants on response to interferon based- direct acting antiviral treatment in difficult-to-treat chronic hepatitis C patients. (2014)
  • Author(s): Nakagawa M, Asahina Y, Taniguchi M, Watanabe T, Nishimura-Sakurai Y, Itsui Y, Azuma S, Kakinuma S, Tanaka Y, Watanabe M.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2014)
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Expression of IFN/.4 in liver and PBMC is closely associated with higher basal expression of ISGs and impaired induction of IL28B by interferon treatment in chronic hepatitis C non-responder patients. (2014)
  • Author(s): Murakawa M, Asahina Y, Nakagawa M, Sakamoto N, Nitta S, Kawai-Kitahata F, Taniguchi M, Watanabe T, Itsui Y, Kakinuma S, Watanabe M.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2014)
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Emergence or selection of resistant associated variant immediately after initiation of the therapy is predictive for failure of direct acting antiviral therapy: ultra-deep sequencing analyses for serial time points. (2014)
  • Author(s): Watanabe T, Asahina Y, Nakagawa M, Kakinuma S, YItsui Y, Taniguchi T, Murakawa M, Nagata H, Miura M, Maekawa S, Enomoto E, Watanabe M.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2014)
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Clinical outcomes in patients who develop hepatocellular carcinoma after hepatitis C viral eradication by antiviral therapy. (2014)
  • Author(s): Tsuchiya K, Yasui Y, Tamaki N, Suzuki S, Hosokawa T, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Asahina Y, Izumi N.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2014)
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Associations of HLA-DPB1 with CHB infection and HBV related HCC in Asia. (2014)
  • Author(s): Nishida N, Sawai H, Asahina Y, Mizokami M, et al.
  • Organizer: The 65th Annual Meeting of the American Association for the Study of Liver Disease (AASLD The Liver Meeting 2014)
  • Place of Presentation: Boston, USA
  • Year and Date: 2014-11-07 – 2014-11-11
• [Presentation] Impaired IL28B gene induction and expression of IFNλ4 influenced by the polymorphisms near IL28B gene are closely associated with a non-response to interferon in chronic hepatitis C patients. (2014)
  • Author(s): Asahina Y, Murakawa M, NittaS, Itsui Y, Nakagawa M, Azuma S, Kakinuma S, Watanabe M.
  • Organizer: The 49th annual meeting of the European association for the study of the liver (EASL The International Liver Congress 2014)
  • Place of Presentation: London, UK
  • Year and Date: 2014-04-08 – 2014-04-14
• [Presentation] Gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid magnetic resonance imaging and contrast enhanced ultrasonography with sonazoid as part of therapeutic strategies for small nonhypervascular hepatic nodular lesions. (2014)
  • Author(s): Tsuchiya K, Yasui Y, Takada N, Nakakuki S, Matsuda S, Kaneko S, Muraoka M, Yamashita N, Hattori N, Tamaki N, Osaki S, Suzuki T, Hosokawa K, Ueda K, Nakanishi H, Itakura J, Takahashi Y, Kurosaki M, Asahina Y, Izumi N.
  • Organizer: The 49th annual meeting of the European association for the study of the liver (EASL The International Liver Congress 2014)
  • Place of Presentation: London, UK
  • Year and Date: 2014-04-08 – 2014-04-14