HCV 感染症におけるトリプトファン代謝酵素による免疫トレランス誘導

• 研究課題/領域番号: 22590730
• 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, 大学院・医学系研究科, 准教授 (70214286)
• 研究分担者: 考藤 達哉 大阪大学, 大学院・医学系研究科, 寄附講座准教授 (80372613) ; 平松 直樹 大阪大学, 大学院・医学系研究科, 講師 (30362700)
• 研究期間 (年度): 2010 – 2012
• 研究課題ステータス: 完了 (2012年度)
• 配分額: 4,420千円 (直接経費: 3,400千円、間接経費: 1,020千円); 2012年度: 1,170千円 (直接経費: 900千円、間接経費: 270千円); 2011年度: 1,170千円 (直接経費: 900千円、間接経費: 270千円); 2010年度: 2,080千円 (直接経費: 1,600千円、間接経費: 480千円)
• キーワード: HCV / IDO / キヌレニン / トリプトファン / 樹状細胞

研究概要

トリプトファン代謝酵素(Indoleamine 2,3-dioxygenase, IDO)は、トリプトファン(Trp)をキヌレニン(Kyn)に代謝し、免疫寛容に寄与する。本研究では、HCV感染患者における免疫機能低下の機序として、 IDOの関与を明らかにすることを目的とした。 検討によって、1)C型肝炎患者では、血漿Kyn濃度は非感染者より高値であり、IDO活性が亢進していること、2)血漿Kyn値は、肝組織でのActivity、Fibrosisと正相関を認めること、3)樹状細胞は炎症刺激によってIDO活性が亢進し、制御性T細胞の誘導に関与すること、 4) IL28B SNP minor群に限っては、血漿Kyn値が低い方がペグIFNα/リバビリン治療によるSVR率は高いことなどが判明した。以上の結果より、 C型慢性肝炎では、肝臓の炎症、線維化の進展にともなってIDO活性が亢進しており、樹状細胞におけるIDO活性の亢進は、制御性T細胞の誘導を増加させることで、HCVの持続感染やペグIFNα/リバビリン治療における難治要因となることが示唆された。

研究成果

• [雑誌論文] Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection (2013)
  • 著者名/発表者名: Higashitani, K., Kanto, T., Kuroda, S., Yoshio, S., Matsubara, T., Kakita, N., Oze, T., Miyazaki, M., Sakakibara, M., Hiramatsu, N., Mita, E., Imai, Y., Kasahara, A., Okuno, A., Takikawa, O., Hayashi, N. and Takehara, T.
  • 雑誌名: J Gastroenterol
  • NAID: 10031177017
• [雑誌論文] Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection. (2013)
  • 著者名/発表者名: Higashitani K
  • 雑誌名: Journal of Gastroenterology 巻: 印刷中
  • 査読あり
• [雑誌論文] Reducing Peg-IFN doses causes later virologic response or no response in HCV genotype 1 patients treated with Peg-IFN alfa-2b plus ribavirin (2012)
  • 著者名/発表者名: Oze, T., Hiramatsu, N., Song, C., Yakushijin, T., Iio, S., Doi, Y., Oshita, M., Hagiwara, H., Mita, E., Ito, T., Inui, Y., Hijioka, T., Tamura, S., Yoshihara, H., Inoue, A., Imai, Y., Hayashi, E., Kato, M., Miyazaki, M., Hosui, A., Miyagi, T., Yoshida, Y.
  • 雑誌名: J Gastroenterol 巻: 47 ページ: 334-342
  • NAID: 10030560255
• [雑誌論文] Dynamics of regulatory T cells and plasmacytoid dendritic cells as immune markers for virological response in pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C patients. (2012)
  • 著者名/発表者名: Kanto, T. *, Inoue, M., Oze, T., Miyazaki, M., Sakakibara, M., Kakita, N., Matsubara, T., Higashitani, K., Hagiwara, H., Iio, S., Katayama, K., Mita, E., Kasahara, A., Hiramatsu, N., Takehara, T. and Hayashi, N.
  • 雑誌名: J Gastroenterol 巻: 47 ページ: 169-178
• [雑誌論文] Reducing Peg-IFN doses causes later virologic response or no response in HCV genotype 1 patients treated with Peg-IFN alfa-2b plus ribavirin (2012)
  • 著者名/発表者名: Oze T.
  • 雑誌名: Journal of Gastroenterology 巻: 47 ページ: 334-342
  • 査読あり
• [雑誌論文] Dynamics of regulatory T cells and plasmacytoid dendritic cells as immune markers for virological response in pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C patients. (2012)
  • 著者名/発表者名: Kanto T
  • 雑誌名: Journal of Gastroenterology 巻: 47 号: 2 ページ: 169-178
  • DOI: 10.1007/s00535-011-0466-y
  • 査読あり
• [雑誌論文] Dynamics of regulatory T cells and plasmacytoid dendritic cells as immune markers for virological response in pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C patients (2012)
  • 著者名/発表者名: Kanto T., Inoue M., et al
  • 雑誌名: Journal of Gastroenterology 巻: 47 ページ: 169-178
  • 査読あり
• [雑誌論文] Indications and limitations for aged patients with chronic hepatitis C in pegylated interferon alfa-2b plus ribavirin combination therapy. (2011)
  • 著者名/発表者名: Oze, T., Hiramatsu, N., Yakushijin, T., Mochizuki, K., Oshita, M., Hagiwara, H., Mita, E., Ito, T., Fukui, H., Inui, Y., Hijioka, T., Inada, M., Kaytayama, K., Tamura, S., Yoshihara, H., Inoue, A., Imai, Y., Kato, M., Miyagi, T., Yoshida, Y., Tatsumi, T.
  • 雑誌名: J Hepatol 巻: 54 ページ: 604-611
• [雑誌論文] The efficacy of exten ded treatment with pegylated interferon plus ribavirin in patients with HCV genotype 1 and slow virologic response in Japan. (2011)
  • 著者名/発表者名: Oze, T., Hiramatsu, N., Yakushijin, T., Mochizuki, K., Imanaka, K., Yamada, A., Oshita, M., Kaneko, A., Hagiwara, H., Mita, E., Ito, T., Nagase, T., Inui, Y., Hijioka, T., Tamura, S., Yoshihara, H., Hayashi, E., Imai, Y., Kato, M., Hosui, A., Miyagi, T.
  • 雑誌名: J Gastroenterol 巻: 46 ページ: 944-952
• [雑誌論文] Amino acid substitution in the core protein has no impact on relapse in hepatitis C genotype 1 patients treated withpeginterferon and ribavirin. (2011)
  • 著者名/発表者名: Inoue, Y., Hiramatsu, N., Oze, T., Yakushijin, T., Mochizuki, K., Fukuda, K., Mita, E., Haruna, Y ., Inoue, A., Imai, Y., Hosui, A., Miyagi, T., Yoshida, Y., Tatsumi, T., Kiso, S., Kanto, T., Kasahara, A., Takehara, T. and Hayashi, N. *
  • 雑誌名: J Med Virol 巻: 83 ページ: 419-427
• [雑誌論文] Efficacy of pegylated interferon plus ribavirin combination therapy for hepatitis C patients with normal ALT levels: a matched case-control study. (2011)
  • 著者名/発表者名: Hiramatsu, N., Inoue, Y., Oze, T., Kurashige, N., Yakushijin, T., Mochizuki, K., Miyagi, T., Tatsumi, T., Kiso, S., Kanto, T., Kasahara, A., Takehara, T., Oshita, M., Mita, E., Hagiwara, H., Inui, Y., Katayama, K., Tamura, S., Yoshihara, H., Imai, Y. and
  • 雑誌名: J Gastroenterol 巻: 46 ページ: 1335-1343
  • NAID: 10030295018
• [雑誌論文] Indications and limitations for aged patients with chronic hepatitis C in pegylated interferon alfa-2b plus ribavirin combination therapy (2011)
  • 著者名/発表者名: Oze, T., Hiramatsu, N, et al
  • 雑誌名: Journal of Hepatology 巻: 54 ページ: 604-611
  • 査読あり
• [雑誌論文] The efficacy of extended treatment with pegylated interferon plus ribavirin in patients with HCV genotype 1 and slow virologic response in Japan (2011)
  • 著者名/発表者名: Oze, T., Hiramatsu, N., et al
  • 雑誌名: Journal of Gastroenterology 巻: 46 ページ: 944-952
  • NAID: 10029313419
  • 査読あり
• [雑誌論文] Amino acid substitution in the core protein has no impact on relapse in hepatitis C genotype 1 patients treated with peginterferon and ribavirin (2011)
  • 著者名/発表者名: Inoue Y, Tatsumi T, et al
  • 雑誌名: Journal of Medical Virology 巻: 83 号: 3 ページ: 419-427
  • DOI: 10.1002/jmv.21975
  • 査読あり
• [雑誌論文] Efficacy of pegylated interferon plus ribavirin combination therapy for hepatitis C patients with normal ALT levels : a matched case-control study (2011)
  • 著者名/発表者名: Hiramatsu, N., Inoue, Y., et al
  • 雑誌名: Journal of Gastroenterology 巻: 46 ページ: 1335-1343
  • NAID: 10030295018
  • 査読あり
• [雑誌論文] Indications and limitations for aged patients with chronic hepatitis C in pegylated interferon alfa-2b plus ribavirin combination therapy. (2011)
  • 著者名/発表者名: Oze, T., Hiramatsu, N., et al.
  • 雑誌名: J Hepatol 巻: (印刷中)
  • 査読あり
• [雑誌論文] Altered interferon-alpha-signaling in natural killer cells from patients with chronic hepatitis C virus infection (2010)
  • 著者名/発表者名: Miyagi, T., Takehara, T. *, Nishio, K., Shimizu, S., Kohga, K., Li, W., Tatsumi, T., Hiramatsu, N., Kanto, T. and Hayashi, N.
  • 雑誌名: J Hepatol 巻: 53 ページ: 424-430
• [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. (2010)
  • 著者名/発表者名: Inoue, Y., Hiramatsu, N., et al.
  • 雑誌名: J Viral Hepatitis 巻: 17 ページ: 336-344
  • 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. (2010)
  • 著者名/発表者名: Imai, Y., Tamura, S., et al.
  • 雑誌名: J Viral Hepatitis 巻: 17 ページ: 185-191
  • 査読あり
• [学会発表] Association of indoleamine 2,3-dioxygenase in dendritic cells with the generation ofregulatory T cells in chronic hepatitis C patients (2012)
  • 著者名/発表者名: Higashitani K, Kanto T, Kuroda S, Yoshio S, Matsubara T, Kakita N, Oze T, Hiramatsu N, Mita E, Imai Y, Kasahara A, Okuno A, Takikawa O, Hayashi N, Takehara T
  • 学会等名: The Liver Meeting AASLD 63rd Annual Meeting and Postgraduate Course
  • 発表場所: Boston, MA, USA
  • 年月日: 2012-11-10
• [学会発表] Association of indoleamine 2,3-dioxygenase in dendritic cells with the generation of regulatory T cells in chronic hepatitis C patients. (2012)
  • 著者名/発表者名: Higashitani K
  • 学会等名: The Liver Meeting AASLD 63rd Annual Meeting and Postgraduate Course
  • 発表場所: Boston, MA USA
• [学会発表] Enhanced ability of IL28A and IL28B induction in plasmacytoid dendritic cells in chronic hepatitis C patients with major allele of IL28B single nucleotide polymorphism. (2011)
  • 著者名/発表者名: Kakita N, Kanto T, Miyazaki M, Yoshio S, Kuroda S, Matsubara T, Higashitani K, Sakakibara M, Hiramatsu N, Kasahara A, Takehara T, Hayashi N
  • 学会等名: The Liver Meeting AASLD 62nd Annual Meeting and Postgraduate Course
  • 発表場所: San Francisco CA, USA
  • 年月日: 2011-11-08
• [学会発表] Enhanced ability of IL28A and IL28B induction in plasmacytoid dendritic cells in chronic hepatitis C patients with major allele of IL28B single nucleotide polymorphism (2011)
  • 著者名/発表者名: Kakita N, Kanto T, et al
  • 学会等名: The Liver Meeting AASLD 62d Annual Meeting and Postgraduate Course
  • 発表場所: San Francisco, CA, USA
  • 年月日: 2011-11-08
• [学会発表] Pro-angiogenic receptor TIE2-expressing monocytes/TEM as novel diagnostic biomarker for hepatocellular carcinoma (2011)
  • 著者名/発表者名: Matsubara T, Kanto T, Kuroda S, Yoshio S, Higashitani K, Kakita N, Miyazaki M, Hiramatsu N, Kasahara A, Takehara T
  • 学会等名: The Liver Meeting AASLD 62nd Annual Meeting and Postgraduate Course
  • 発表場所: San Francisco CA, USA
  • 年月日: 2011-11-07
• [学会発表] Pro-angiogenic receptor TIE2-expressing monocytes/TEM as novel diagnostic biomarker for hepatocellular carcinoma (2011)
  • 著者名/発表者名: Matsubara T, Kanto T, et al
  • 学会等名: The Liver Meeting AASLD 62d Annual Meeting and Postgraduate Course
  • 発表場所: San Francisco, CA, USA
  • 年月日: 2011-11-07
• [学会発表] Viral suppression at week 4 exceeds the IL28B SNP for predicting SVR in pegylated interferon plus ribavirin combination therapy of genotype 1 infected patients with chronic hepatitis. (2011)
  • 著者名/発表者名: Oze T, Hiramatsu N, Yakushijin T, Doi Y, Ogawa H, Hagiwara H, Mita E, Kaneko A, Katayama K, Hijioka T, Tamura S, Yoshihara H, Inoue A, Imai Y, Hayashi E, Hosui A, Miyagi T, Yoshida Y, Tatsumi T, Kiso S, Kanto T, Kasahara A, Hayashi N, Takehara T.
  • 学会等名: The Liver Meeting AASLD 62nd Annual Meeting and Postgraduate Course
  • 発表場所: San Francisco CA, USA
  • 年月日: 2011-11-06
• [学会発表] Estimation of liver fibrosis by VTTQ (Virtual tissue touch quantification in chronic liver disease: the usefulness of VS/PLT (2011)
  • 著者名/発表者名: Yamada R, Hiramatsu N, Oze T, Harada N, Song C, Inoue Y, Kurokawa M, Miyazaki M, Yakushijin T, Hosui A, Miyagi T, Tatsumi T, Kiso S, Kanto T, Kasahara A, Hayashi N, Takehara T
  • 学会等名: The Liver Meeting AASLD 62nd Annual Meeting and Postgraduate Course
  • 発表場所: San Francisco CA, USA
  • 年月日: 2011-11-06
• [学会発表] Viral suppression at week 4 exceeds the IL28B SNP for predicting SVR in pegylated interferon plus ribavirin combination therapy of genotype 1 infected patients with chronic hepatitis C (2011)
  • 著者名/発表者名: Oze T, Hiramatsu N, et al
  • 学会等名: The Liver Meeting AASLD 62d Annual Meeting and Postgraduate Course
  • 発表場所: San Francisco, CA, USA
  • 年月日: 2011-11-06
• [学会発表] Estimation of liver fibrosis by VTTQ (virtual tissue touch quantification) in chronic liver disease : The usefulness of Vs/plt (2011)
  • 著者名/発表者名: Yamada R, Hiramatsu N, et al
  • 学会等名: The Liver Meeting AASLD 62d Annual Meeting and Postgraduate Course
  • 発表場所: San Francisco, CA, USA
  • 年月日: 2011-11-06
• [学会発表] Active role of tryptophan catalyzing enzyme, indoleamine 2, 3-dioxygenase, in the generation of regulatory T cells in chronic hepatitis C patients (2010)
  • 著者名/発表者名: Higashitani K, Kanto T, Miyazaki M, Inoue M, Matsubara T, Kakita N, Itose I, Sakakibara M, Hiramatsu N, Takehara T, Kasahara A, Hayashi N
  • 学会等名: The Liver Meeting AASLD 61stAnnual Meeting and Postgraduate Course
  • 発表場所: Boston MA
  • 年月日: 2010-10-30
• [学会発表] Indoleamine 2, 3-dioxygenase as an active inducer of regulatory T cells in chronic HCV infection (2010)
  • 著者名/発表者名: Higashitani K, Kanto T, Miyazaki M, Inoue M, Matsubara T, Kakita N, Itose I, Sakakibara M, Hiramatsu N, Takehara T, Kasahara A, Hayashi N
  • 学会等名: 17thInternational Meeting on Hepatitis C virus and related viruses
  • 発表場所: Yokohama Japan
  • 年月日: 2010-09-11
• [学会発表] Active role of teyptophan catalyzing enzyme, indoleamine 2,3-dioxygenase, in the generation of regulatory T cells in chronic hepatitis C patients (2010)
  • 著者名/発表者名: Higashitani K, Kanto T, et al.
  • 学会等名: The Liver Meeting AASLD 61st Annual Meeting and Postgraduate Course
  • 発表場所: Boston, MA, USA
• [学会発表] Crucial roles of IL-10-producing Type 1 regulatory T cells (Tr1) in the pathogenesis of hepatitis C virus-infected hepatocellular carcinoma (2010)
  • 著者名/発表者名: Kakita N, Kanto T, et al.
  • 学会等名: 17^<th> International Meeting on Hepatitis C virus and related viruses
  • 発表場所: Yokohama, Japan
• [学会発表] Indoleamine 2,3-dioxygenase as an active inducer of regulatory T cells in chronic HCV infection (2010)
  • 著者名/発表者名: Higashitani K, Kanto T, et al.
  • 学会等名: 17^<th> International Meeting on Hepatitis C virus and related viruses
  • 発表場所: Yokohama, Japan
• [学会発表] Type-I and type-III interferon induction from myeloid and plasmacytoid dendritic cells in chronic hepatitis C patients ; lack of association with single nucleotide polymorphism near IL28B gene (2010)
  • 著者名/発表者名: Miyazaki M, Kanto T, et al.
  • 学会等名: 17^<th> International Meeting on Hepatitis C virus and related viruses
  • 発表場所: Yokohama, Japan
• [備考] 大阪大学大学院医学系研究科消化器内科学ホームページ
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/index.htm
• [備考] 大阪大学大学院医学系研究科消化器内科学
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/index.htm
• [備考]
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/index.htm
• [備考]
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/index.htm