難治性C型肝炎に対する細胞免疫制御に基づく個別化治療の開発

2009 年度 研究成果報告書

• 研究課題/領域番号: 19590764
• 研究種目: 基盤研究(C)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 消化器内科学
• 研究機関: 大阪大学
• 研究代表者: 笠原 彰紀 大阪大学, 医学系研究科, 准教授 (70214286)
• 研究分担者: 考藤 達哉 大阪大学, 医学系研究科, 寄附講座准教授 (80372613) ; 平松 直樹 大阪大学, 医学系研究科, 講師 (30362700)
• 研究期間 (年度): 2007 – 2009
• キーワード: C型肝炎 / ペグインターフェロンα / リバビリン / 樹状細胞 / 制御性T細胞

研究概要

C型慢性肝炎患者に対するPEG-IFNα/リバビリン併用療法において、樹状細胞(DC)などの免疫細胞頻度・機能と治療効果との関連を検討した。単変量解析ではミエロイドDC頻度、終了時DC機能が、多変量解析では血小板数とプラスマサイトイドDC頻度が、独立したSVR規定因子として抽出された。PEG-IFNα/リバビリン併用療法において、免疫細胞マーカーに基づく個別化治療が可能になる可能性が示された。

研究成果

• [雑誌論文] Enhanced ability of regulatory T cells in chronic hepatitis C patients with persistently normal alanine aminotransferase levels than those with active hepatitis (2009)
  • 著者名/発表者名: Itose, I., Kanto, T. Kakita, N., Takebe, S., Inoue, M., Higashitani, K., Miyazaki, M., Miyatake, H., Sakakibara, M., Hiramatsu, N., Takehara, T., Kasahara, A., Hayashi, N.
  • 雑誌名: than those with active hepatitis. Journal of Viral Hepatitis 16 ページ: 846-852
  • 査読あり
• [雑誌論文] Ribavirin dose reduction raises relapse rate dose-dependently in genotype 1 patients with hepatitis C responding to pegylated interferon alpha-2b plus ribavirin (2009)
  • 著者名/発表者名: Hiramatsu, N., Oze, T Yakushijin, T., Inoue, Y., Igura, T., Mochizuki, K., Imanaka, K., Kaneko, A., Oshita, M., Hagiwara, H., Mita, E., Nagase, T., Ito, T., Inui, Y., Hijioka, T., Katayama, K., Tamura, S., Yoshihara, H., Imai, Y., Kato, M., Yoshida, Y., THiramatsu, N., Oze, T Yakushijin, T., Inoue, Y., Igura, T., Mochizuki, K., Imanaka, K
  • 雑誌名: Journal of Viral Hepatitis 16 ページ: 586-594
  • 査読あり
• [雑誌論文] Two types of drug-resistant hepatitis B viral strains emerging alternately and their susceptibility to combination therapy with entecavir and adefovir Antiviral Therapy (2009)
  • 著者名/発表者名: Kurashige N., Ohkawa, K Hiramatsu, N., Oze, T., Yakushijin, T., Mochizuki, K., Hosui, A., Miyagi, T., Ishida, H., Tatsumi, T., Kanto, T., Takehara, T., Hayashi, N.
  • 雑誌名: 14 ページ: 873-877
  • 査読あり
• [雑誌論文] Reduced risk of hepatocellular carcinoma after interferon therapy in aged patients with chronic hepatitis C is limited to sustained virological responders (2009)
  • 著者名/発表者名: Imai, Y., Tamura, S.,. Tanaka, H., Hiramatsu, N., Kiso, Y., Doi, Y., Inada, M., Nagase, T., Kitada, T., Imanaka, K., Fukuda, K., Takehara, T., Kasahara, A., Hayashi, N.
  • 雑誌名: Journal of Viral Hepatitis (in press)
  • 査読あり
• [雑誌論文] Molecular insights into (beta)-galactoside (alpha)2, 6-sialyltransferase secretion in vivo (2009)
  • 著者名/発表者名: Kitazume, S., Oka, R. Ogawa, K., Futakawa, S., Hagiwara, Y., Takigawa, H., Kato, M., Kasahara, A., Miyoshi, E., Taniguchi, N., Hashimoto, Y.
  • 雑誌名: Glycobiology 19 ページ: 479-487
  • 査読あり
• [雑誌論文] Factors affecting efficacy in patients with genotype 2 chronic hepatitis C treated by pegylated interferon alpha-2b and ribavirin: reducing drug doses has no impact on rapid and susutained virological responses (2009)
  • 著者名/発表者名: Inoue, Y., Hiramatsu, N, Oze, T., Yakushijin, T., Mochizuki, K., Hagiwara, H., Oshita, M., Mita, E., Fukui, H., Inada, M., Tamura, S., Yoshihara, H., Hyashi, E., Inoue, A., Imai, Y., Kato, M., Miyagi, T., Hohsui, A., Ishida, M., Kiso, S., Kanto, T., KasahInoue, Y., Hiramatsu, N, Oze, T., Y
  • 雑誌名: Journal of Viral Hepatitis (in press)
  • 査読あり
• [雑誌論文] Effect of interferon alpha-2b plus ribavirine therapy on incidence of hepatocellular carcinoma in patients with chronic hepatitis (2009)
  • 著者名/発表者名: Kurokawa, M., Hiramatsu, M Oze, T., Mochizuki, K., Yakushijin, T., Kurashige, N., Inoue, Y., Igura, T., Imanaka, K., Yamada, A., Oshita, M., Hagiwara, H., Mita, E., Ito, T., Inui, Y., Hijioka, T., Yoshihara, H., Inoue, A., Imai, Y., Kato, M., Kiso, S., KaKurokawa, M., Hiramatsu, M Oze, T., Mochizuki, K.
  • 雑誌名: Hepatology Research 39 ページ: 432-438
  • 査読あり
• [雑誌論文] Lamivudine-to-entecavir switching treatment in type B chronic hepatitis patients without evidence of lamivudine resistance (2009)
  • 著者名/発表者名: Kurashige, N., Ohkawa K. Hiramatsu, N., Yakushijin, T., Mochizuki, K., Oze, T., Kiso, S., Kanto, T., Takehara, T., Kasahara, A., Doi, Y., Yamada, A., Fukuda, K., Oshita, M., Mita, E., Fukui, H., Nagase, T., Yoshihara, H., Imai, Y., Kato, M., Kashihara, T. Kurashige, N
  • 雑誌名: Journal of Gastroenterology 44 ページ: 864-870
  • 査読あり
• [雑誌論文] Repeated administration of recombinant human serum albumin caused no serious allergic reactions in patients with liver cirrhosis-a multicenter clinical study Journal of Gastroenterology (2008)
  • 著者名/発表者名: Kasahara A, Kita K., Tomita E, Toyota J, Imai Y, Kumada H.
  • 雑誌名: 43 ページ: 464-472
  • 査読あり
• [雑誌論文] Declining incidence of hepatocellular carcinoma in Osaka, Japan, from 1990-2003 (2008)
  • 著者名/発表者名: Tanaka H., Imai Y. Hiramatsu N, Ito Y, Imanaka K, Oshita M, Hijioka T, Katayama K, Yabuuchi I, Yoshihara H, Inoue A, Kato M, Takehara T, Tamura S, Kasahara A, Hayashi N, Tsukuma H.
  • 雑誌名: Annals of Internal Medicine 148 ページ: 820-826
  • 査読あり
• [雑誌論文] Site-specific analysis of N-glycans on haptoglobin in sera of patients with pancreatic cancer: A novel approach for the development of tumor markers (2008)
  • 著者名/発表者名: Nakano M., Nakagawa T. Ito T, Kitada T, Hijioka T, Kasahara A, Tajiri M, Wada Y, Taniguchi N, Miyoshi E.
  • 雑誌名: nternational Journal of Cancer 122 ページ: 2301-2309
  • 査読あり
• [雑誌論文] Early decline of hemoglobin can predict progression of hemolytic anemia during pegylated interferon and ribavirin combination therapy in patients with chronic hepatitis C (2008)
  • 著者名/発表者名: iramatsu N, Kurashige N, Oze T, Takehara T, Tamura S, Kasahara A, Oshita M, Katayama K, Yoshihara H, Imai Y, Kato M, Kawata S, Tsubouchi H, Kumada H, Okanoue T, Kakumu S, Hayashi N.
  • 雑誌名: Hepatology Research 38 ページ: 52-59
  • 査読あり
• [雑誌論文] Impaired cytokine response in myeloid dendritic cells in chronic hepatitis C virusinfection regardless of enhanced expression of Toll-like receptors and retinoic acid inducible gene-I Journal of Medical Virology (2008)
  • 著者名/発表者名: Miyazaki M., Kanto T., Inoue, M., Itose, I., Miyatake, H., Sakakibara, M., Yakushijin, T., Kakita, N., Hiramatsu, N., Takehara, T., Kasahara, A., Hayashi, N.
  • 雑誌名: 80 ページ: 980-988
  • 査読あり
• [雑誌論文] new prognostic system for hepatocellular carcinoma including recurrent cases: a study of 861 patients in a single institution (2008)
  • 著者名/発表者名: Toyama T., Hiramatsu N. Yakushijin, T., Oze, T., Nakanishi, F., Yasumaru, M., Mochizuki, K., Kanto, T., Takehara, T., Kasahara, A., Hayashi, N.
  • 雑誌名: Journal of Clinical Gastroenterology 42 ページ: 317-322
  • 査読あり
• [雑誌論文] Initial viral response is the most powerful predictor of the emergence of YMDD mutant virus in chronic hepatitis B patients treated with lamivudine (2008)
  • 著者名/発表者名: Kurashige N., Hiramatsu N. Ohkawa, K., Oze, T., Inoue, Y., Kurokawa, M., Yakushijin, T., Igura, T., Kiso, S., Kanto, T., Takehara, T., Tamura, S., Kasahara, A., Oshita, M., Hijioka, T., Katayama, K., Yoshihara, H., Hayashi, E., Imai, Y., Kato, M., HayashiKura
  • 雑誌名: Hepatology Research 38 ページ: 450-456
  • 査読あり
• [雑誌論文] Impaired ability of interferon-alpha-primed dendritic cells to stimulate Th1-type CD4 T cell response in chronic hepatitis C virus infection (2007)
  • 著者名/発表者名: Miyatake H., Kanto T., Inoue, M., Sakakibara, M., Kaimori, A., Yakushijin, T., Itose, I., Miyazaki, M., Kuzushita, N., Hiramatsu, N., Takehara, T., Kasahara, A., Hayashi, N.
  • 雑誌名: Journal of Viral Hepatitis 14 ページ: 404-412
  • 査読あり
• [雑誌論文] Involvement of dendritic cell frequency and function in virological relapse in pegylated interferon-α2b and ribavirin therapy for chronic hepatitis C patients (2007)
  • 著者名/発表者名: Itose I., Kanto T., Inoue, M., Miyazaki, M., Miyatake, H., Sakakibara, M., Yakushijin, T., Oze, T., Hiramatsu, N., Takehara, T., Kasahara, A., Hayashi, N.
  • 雑誌名: ournal of Medical Virology 79 ページ: 511-521
  • 査読あり
• [雑誌論文] Innate immunity in hepatitis C virus infection: Interplay amongdendritic cells, natural killer cells and natural killer T cells (2007)
  • 著者名/発表者名: Jinushi, M., Takehara, T., Tatsumi, T., Yamaguchi, S., Sakamori, R., Hiramatsu, N., Kanto, T., Ohkawa, K., Hayashi, N
  • 雑誌名: Hepatolgy Reseach 37 Suppl 3S ページ: 319-326
  • 査読あり
• [雑誌論文] Natural killer cell and hepatic cell interaction via NKG2A leads to dendritic cell-mediated induction of CD4 CD25 T cells with PD-1-dependent regulatory activities Immunology (2007)
  • 著者名/発表者名: Jinushi, M., Takehara, T., Tatsumi, T., Yamaguchi, S., Sakamori, R., Hiramatsu, N., Kanto, T., Ohkawa, K., Hayashi, N
  • 雑誌名: 120 ページ: 73-82
  • 査読あり
• [学会発表] Dynamics of plasmacytoid dendritic cells as a predictor of relapse regardless of virological response in pegylated interferon-a and ribavirin therapy in chronic hepatitis C patients (2009)
  • 著者名/発表者名: Kanto T
  • 学会等名: The Liver Meeting AASLD 60th Annual Meeting and Postgraduate Course
  • 発表場所: Boston, MA, USA
  • 年月日: 20091030-20091103
• [学会発表] Feasibility of IL-10-producing regulatory Type 1 cells for the monitoring of viable hepatocellular carcinoma through local ablation therapy (2009)
  • 著者名/発表者名: Kakita N, Kanto T
  • 学会等名: The Liver Meeting AASLD 60th Annual Meeting and Postgraduate Course
  • 発表場所: Boston, MA, USA
  • 年月日: 20091030-20091103
• [学会発表] Myeloid dendritic cells as a therapeutic target for immune restoration by HCV NS3 protease inhibitor in chronic hepatitis C patients (2009)
  • 著者名/発表者名: Miyazaki M, Kanto T
  • 学会等名: The Liver Meeting AASLD 60th Annual Meeting and Postgraduate Course
  • 発表場所: Boston, MA, USA
  • 年月日: 20091030-20091103
• [学会発表] Reduced drug doses in genotype 1 patients with chronic hepatitis C during treatment with pegylated interferon alfa-2B plus ribavirin delays the timing of HCVRNA negativity or prevents its attainment; A propensity score-matched study (2009)
  • 著者名/発表者名: Son C, Hiramatsu N
  • 学会等名: he Liver Meeting AASLD 60th Annual Meeting and Postgraduate Course
  • 発表場所: Boston, MA, USA
  • 年月日: 20091030-20091103
• [学会発表] Prediction of early response to pegylated interferon and ribavirin in chronic hepatitis C based on amino acid substitutions in the viral core region (2009)
  • 著者名/発表者名: Inoue Y, Hiramatsu N
  • 学会等名: The Liver Meeting AASLD 60th Annual Meeting and Postgraduate Course
  • 発表場所: Boston, MA, USA
  • 年月日: 20091030-20091103
• [学会発表] Factors affecting efficacy in patients with genotype 2 chronic hepatitis C treated by pegylated interferon alfa-2B and ribavirin: reducing drug doses has no impact on rapid and sustained virological responses (2009)
  • 著者名/発表者名: Inoue Y, Hiramatsu N
  • 学会等名: The Liver Meeting AASLD 60th Annual Meeting and Postgraduate Course
  • 発表場所: Boston, MA, USA
  • 年月日: 20091030-20091103
• [学会発表] Dendritic cell as a versatile controller of innate and adaptive immune response against hepatitis C virus (2008)
  • 著者名/発表者名: Kanto T
  • 学会等名: The 10th International Symposium on Dendritic Cells
  • 発表場所: Kobe, Japan
  • 年月日: 20081001-20081005
• [学会発表] Impaired TLR/RIG-I-mediated innate immunity in myeloid dendritic cells in chronic hepatitis C patients (2008)
  • 著者名/発表者名: Miyazaki M. Kanto T
  • 学会等名: The 10th International Symposium on Dendritic Cells
  • 発表場所: Kobe, Japan
  • 年月日: 20081001-20081005
• [学会発表] Dynamic changes of regulatory T cell subsets in patients with chronic HCV infection in relation to the degree of liver inflammation (2008)
  • 著者名/発表者名: Itose I., Kanto T
  • 学会等名: The 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
  • 発表場所: San Francisco, CA. USA
  • 年月日: 2008-11-02
• [学会発表] IL-7 as a booster of Th2-differentiation by modulating myeloid dendritic cells in chronic hepatitis C virus infection (2008)
  • 著者名/発表者名: Takebe S., Kanto T
  • 学会等名: The 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
  • 発表場所: San Francisco, CA. USA
  • 年月日: 2008-11-02
• [学会発表] Natural regulatory T cells as biomarker for the assessment of hepatocellular carcinoma in local ablation therapy (2008)
  • 著者名/発表者名: Kakita N., Kanto T
  • 学会等名: The 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
  • 発表場所: San Francisco, CA. USA
  • 年月日: 2008-11-02
• [学会発表] Effect of interferon alfa-2b plus ribavirin therapy on incidence of hepatocellular carcinoma in patients with chronic hepatitis (2008)
  • 著者名/発表者名: Kurokawa M., Hiramatsu N
  • 学会等名: The 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
  • 発表場所: San Francisco, CA. USA
  • 年月日: 2008-11-02
• [学会発表] Extended treatment with peginterferon alfa-2b and ribavirin combination therapy can suppress the relapse rate after treatment of chronic hepatitis C genotype 1 patients with late viral relapse (2008)
  • 著者名/発表者名: Oze T., Hiramatsu N
  • 学会等名: The 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
  • 発表場所: San Francisco, CA. USA
  • 年月日: 2008-11-02
• [学会発表] Ribavirin dosage reduction raises relapse rate dose-dependently in genotype 1 patients with chronic hepatitis C responding to pegylated interferon alfa-2b plus ribavirin (2008)
  • 著者名/発表者名: Oze T., Hiramatsu N
  • 学会等名: The 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD)
  • 発表場所: San Francisco, CA. USA
  • 年月日: 2008-11-02
• [備考]
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/index.htm