Investigation for the mechanisms of immune tolerance against HCV mediated by tryptophan-catalyzing enzyme, IDO

• Project/Area Number: 22590730
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Osaka University
• Principal Investigator: KASAHARA Akinori 大阪大学, 大学院・医学系研究科, 准教授 (70214286)
• Co-Investigator(Kenkyū-buntansha): KANTO Tatsuya 大阪大学, 大学院・医学系研究科, 寄附講座准教授 (80372613) ; HIRAMATSU Naoki 大阪大学, 大学院・医学系研究科, 講師 (30362700)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2012: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2011: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2010: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: HCV / IDO / キヌレニン / トリプトファン / 樹状細胞

Research Abstract

A tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase (IDO), is reported to be an inducer of immune tolerance. Our aim was to clarify whether IDO is activated or not in chronic hepatitis C patients (CHC) and its role in immune responses. Serum kynurenine concentration in CHC patients was significantly higher than those in healthy donors, the levels of which were positively correlated with histological activity or fibrosis scores. IDO activity in IDO-DCs from the patients was significantly higher than those from the donors. Furthermore, IDO-DCs from the patients induced more regulatory T cells (Tregs) compared to those from donors. In patients with IL28B minor genotype, Kyn concentration was lower in SVR patients in Peg-IFNα/ribavirin therapy than those in non -SVR patients.In conclusion, systemic IDO activity is enhanced in CHC patients in correlation with the degree of liver inflammation and fibrosis. IDO-DCs from the patients are prone to induce Tregs, resulting in HCV persistence or the resistance to IFN-based therapy.

Research Products

• [Journal Article] 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)
  • Author(s): 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.
  • Journal Title: J Gastroenterol
  • NAID: 10031177017
• [Journal Article] 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)
  • Author(s): Higashitani K
  • Journal Title: Journal of Gastroenterology Volume: 印刷中
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): 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.
  • Journal Title: J Gastroenterol Volume: 47 Pages: 334-342
  • NAID: 10030560255
• [Journal Article] 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)
  • Author(s): 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.
  • Journal Title: J Gastroenterol Volume: 47 Pages: 169-178
• [Journal Article] 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)
  • Author(s): Oze T.
  • Journal Title: Journal of Gastroenterology Volume: 47 Pages: 334-342
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): Kanto T
  • Journal Title: Journal of Gastroenterology Volume: 47 Issue: 2 Pages: 169-178
  • DOI: 10.1007/s00535-011-0466-y
  • Peer Reviewed
• [Journal Article] 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)
  • Author(s): Kanto T., Inoue M., et al
  • Journal Title: Journal of Gastroenterology Volume: 47 Pages: 169-178
  • Peer Reviewed
• [Journal Article] Indications and limitations for aged patients with chronic hepatitis C in pegylated interferon alfa-2b plus ribavirin combination therapy. (2011)
  • Author(s): 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.
  • Journal Title: J Hepatol Volume: 54 Pages: 604-611
• [Journal Article] The efficacy of exten ded treatment with pegylated interferon plus ribavirin in patients with HCV genotype 1 and slow virologic response in Japan. (2011)
  • Author(s): 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.
  • Journal Title: J Gastroenterol Volume: 46 Pages: 944-952
• [Journal Article] Amino acid substitution in the core protein has no impact on relapse in hepatitis C genotype 1 patients treated withpeginterferon and ribavirin. (2011)
  • Author(s): 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. *
  • Journal Title: J Med Virol Volume: 83 Pages: 419-427
• [Journal Article] Efficacy of pegylated interferon plus ribavirin combination therapy for hepatitis C patients with normal ALT levels: a matched case-control study. (2011)
  • Author(s): 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
  • Journal Title: J Gastroenterol Volume: 46 Pages: 1335-1343
  • NAID: 10030295018
• [Journal Article] Indications and limitations for aged patients with chronic hepatitis C in pegylated interferon alfa-2b plus ribavirin combination therapy (2011)
  • Author(s): Oze, T., Hiramatsu, N, et al
  • Journal Title: Journal of Hepatology Volume: 54 Pages: 604-611
  • Peer Reviewed
• [Journal Article] The efficacy of extended treatment with pegylated interferon plus ribavirin in patients with HCV genotype 1 and slow virologic response in Japan (2011)
  • Author(s): Oze, T., Hiramatsu, N., et al
  • Journal Title: Journal of Gastroenterology Volume: 46 Pages: 944-952
  • NAID: 10029313419
  • Peer Reviewed
• [Journal Article] Amino acid substitution in the core protein has no impact on relapse in hepatitis C genotype 1 patients treated with peginterferon and ribavirin (2011)
  • Author(s): Inoue Y, Tatsumi T, et al
  • Journal Title: Journal of Medical Virology Volume: 83 Issue: 3 Pages: 419-427
  • DOI: 10.1002/jmv.21975
  • Peer Reviewed
• [Journal Article] Efficacy of pegylated interferon plus ribavirin combination therapy for hepatitis C patients with normal ALT levels : a matched case-control study (2011)
  • Author(s): Hiramatsu, N., Inoue, Y., et al
  • Journal Title: Journal of Gastroenterology Volume: 46 Pages: 1335-1343
  • NAID: 10030295018
  • Peer Reviewed
• [Journal Article] Indications and limitations for aged patients with chronic hepatitis C in pegylated interferon alfa-2b plus ribavirin combination therapy. (2011)
  • Author(s): Oze, T., Hiramatsu, N., et al.
  • Journal Title: J Hepatol Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Altered interferon-alpha-signaling in natural killer cells from patients with chronic hepatitis C virus infection (2010)
  • Author(s): Miyagi, T., Takehara, T. *, Nishio, K., Shimizu, S., Kohga, K., Li, W., Tatsumi, T., Hiramatsu, N., Kanto, T. and Hayashi, N.
  • Journal Title: J Hepatol Volume: 53 Pages: 424-430
• [Journal Article] 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)
  • Author(s): Inoue, Y., Hiramatsu, N., et al.
  • Journal Title: J Viral Hepatitis Volume: 17 Pages: 336-344
  • Peer Reviewed
• [Journal Article] Reduced risk of hepatocellular carcinoma after interferon therapy in aged patients with chronic hepatitis C is limited to sustained virological responders. (2010)
  • Author(s): Imai, Y., Tamura, S., et al.
  • Journal Title: J Viral Hepatitis Volume: 17 Pages: 185-191
  • Peer Reviewed
• [Presentation] Association of indoleamine 2,3-dioxygenase in dendritic cells with the generation ofregulatory T cells in chronic hepatitis C patients (2012)
  • Author(s): 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
  • Organizer: The Liver Meeting AASLD 63rd Annual Meeting and Postgraduate Course
  • Place of Presentation: Boston, MA, USA
  • Year and Date: 2012-11-10
• [Presentation] Association of indoleamine 2,3-dioxygenase in dendritic cells with the generation of regulatory T cells in chronic hepatitis C patients. (2012)
  • Author(s): Higashitani K
  • Organizer: The Liver Meeting AASLD 63rd Annual Meeting and Postgraduate Course
  • Place of Presentation: Boston, MA USA
• [Presentation] 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)
  • Author(s): Kakita N, Kanto T, Miyazaki M, Yoshio S, Kuroda S, Matsubara T, Higashitani K, Sakakibara M, Hiramatsu N, Kasahara A, Takehara T, Hayashi N
  • Organizer: The Liver Meeting AASLD 62nd Annual Meeting and Postgraduate Course
  • Place of Presentation: San Francisco CA, USA
  • Year and Date: 2011-11-08
• [Presentation] 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)
  • Author(s): Kakita N, Kanto T, et al
  • Organizer: The Liver Meeting AASLD 62d Annual Meeting and Postgraduate Course
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2011-11-08
• [Presentation] Pro-angiogenic receptor TIE2-expressing monocytes/TEM as novel diagnostic biomarker for hepatocellular carcinoma (2011)
  • Author(s): Matsubara T, Kanto T, Kuroda S, Yoshio S, Higashitani K, Kakita N, Miyazaki M, Hiramatsu N, Kasahara A, Takehara T
  • Organizer: The Liver Meeting AASLD 62nd Annual Meeting and Postgraduate Course
  • Place of Presentation: San Francisco CA, USA
  • Year and Date: 2011-11-07
• [Presentation] Pro-angiogenic receptor TIE2-expressing monocytes/TEM as novel diagnostic biomarker for hepatocellular carcinoma (2011)
  • Author(s): Matsubara T, Kanto T, et al
  • Organizer: The Liver Meeting AASLD 62d Annual Meeting and Postgraduate Course
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2011-11-07
• [Presentation] 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)
  • Author(s): 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.
  • Organizer: The Liver Meeting AASLD 62nd Annual Meeting and Postgraduate Course
  • Place of Presentation: San Francisco CA, USA
  • Year and Date: 2011-11-06
• [Presentation] Estimation of liver fibrosis by VTTQ (Virtual tissue touch quantification in chronic liver disease: the usefulness of VS/PLT (2011)
  • Author(s): 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
  • Organizer: The Liver Meeting AASLD 62nd Annual Meeting and Postgraduate Course
  • Place of Presentation: San Francisco CA, USA
  • Year and Date: 2011-11-06
• [Presentation] 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)
  • Author(s): Oze T, Hiramatsu N, et al
  • Organizer: The Liver Meeting AASLD 62d Annual Meeting and Postgraduate Course
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2011-11-06
• [Presentation] Estimation of liver fibrosis by VTTQ (virtual tissue touch quantification) in chronic liver disease : The usefulness of Vs/plt (2011)
  • Author(s): Yamada R, Hiramatsu N, et al
  • Organizer: The Liver Meeting AASLD 62d Annual Meeting and Postgraduate Course
  • Place of Presentation: San Francisco, CA, USA
  • Year and Date: 2011-11-06
• [Presentation] Active role of tryptophan catalyzing enzyme, indoleamine 2, 3-dioxygenase, in the generation of regulatory T cells in chronic hepatitis C patients (2010)
  • Author(s): Higashitani K, Kanto T, Miyazaki M, Inoue M, Matsubara T, Kakita N, Itose I, Sakakibara M, Hiramatsu N, Takehara T, Kasahara A, Hayashi N
  • Organizer: The Liver Meeting AASLD 61stAnnual Meeting and Postgraduate Course
  • Place of Presentation: Boston MA
  • Year and Date: 2010-10-30
• [Presentation] Indoleamine 2, 3-dioxygenase as an active inducer of regulatory T cells in chronic HCV infection (2010)
  • Author(s): Higashitani K, Kanto T, Miyazaki M, Inoue M, Matsubara T, Kakita N, Itose I, Sakakibara M, Hiramatsu N, Takehara T, Kasahara A, Hayashi N
  • Organizer: 17thInternational Meeting on Hepatitis C virus and related viruses
  • Place of Presentation: Yokohama Japan
  • Year and Date: 2010-09-11
• [Presentation] Active role of teyptophan catalyzing enzyme, indoleamine 2,3-dioxygenase, in the generation of regulatory T cells in chronic hepatitis C patients (2010)
  • Author(s): Higashitani K, Kanto T, et al.
  • Organizer: The Liver Meeting AASLD 61st Annual Meeting and Postgraduate Course
  • Place of Presentation: Boston, MA, USA
• [Presentation] Crucial roles of IL-10-producing Type 1 regulatory T cells (Tr1) in the pathogenesis of hepatitis C virus-infected hepatocellular carcinoma (2010)
  • Author(s): Kakita N, Kanto T, et al.
  • Organizer: 17^<th> International Meeting on Hepatitis C virus and related viruses
  • Place of Presentation: Yokohama, Japan
• [Presentation] Indoleamine 2,3-dioxygenase as an active inducer of regulatory T cells in chronic HCV infection (2010)
  • Author(s): Higashitani K, Kanto T, et al.
  • Organizer: 17^<th> International Meeting on Hepatitis C virus and related viruses
  • Place of Presentation: Yokohama, Japan
• [Presentation] 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)
  • Author(s): Miyazaki M, Kanto T, et al.
  • Organizer: 17^<th> International Meeting on Hepatitis C virus and related viruses
  • Place of Presentation: Yokohama, Japan
• [Remarks] 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
• [Remarks] 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
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/index.htm
• [Remarks]
  • URL: http://www.med.osaka-u.ac.jp/pub/gh/index.htm