Journal of Gastroenterology

, Volume 48, Issue 5, pp 660–670

Association of enhanced activity of indoleamine 2,3-dioxygenase in dendritic cells with the induction of regulatory T cells in chronic hepatitis C infection

Authors

  • Koyo Higashitani
    • Department of Gastroenterology and HepatologyOsaka University Graduate School of Medicine
    • Department of Gastroenterology and HepatologyOsaka University Graduate School of Medicine
  • Shoko Kuroda
    • Department of Gastroenterology and HepatologyOsaka University Graduate School of Medicine
  • Sachiyo Yoshio
    • Department of Gastroenterology and HepatologyOsaka University Graduate School of Medicine
  • Tokuhiro Matsubara
    • Department of Gastroenterology and HepatologyOsaka University Graduate School of Medicine
  • Naruyasu Kakita
    • Department of Gastroenterology and HepatologyOsaka University Graduate School of Medicine
  • Tsugiko Oze
    • Department of Gastroenterology and HepatologyOsaka University Graduate School of Medicine
  • Masanori Miyazaki
    • Department of Gastroenterology and HepatologyOsaka University Graduate School of Medicine
  • Mitsuru Sakakibara
    • Osaka Medical Center for Cancer and Cardiovascular Diseases
  • Naoki Hiramatsu
    • Department of Gastroenterology and HepatologyOsaka University Graduate School of Medicine
  • Eiji Mita
    • National Hospital Organization Osaka National Hospital
  • Yasuharu Imai
    • Ikeda Municipal Hospital
  • Akinori Kasahara
    • Department of General MedicineOsaka University Hospital
  • Alato Okuno
    • Laboratory of Radiation SafetyNational Center for Geriatrics and Gerontology
  • Osamu Takikawa
    • Laboratory of Radiation SafetyNational Center for Geriatrics and Gerontology
  • Norio Hayashi
    • Kansai Rosai Hospital
  • Tetsuo Takehara
    • Department of Gastroenterology and HepatologyOsaka University Graduate School of Medicine
Original Article—Liver, Pancreas, and Biliary Tract

DOI: 10.1007/s00535-012-0667-z

Cite this article as:
Higashitani, K., Kanto, T., Kuroda, S. et al. J Gastroenterol (2013) 48: 660. doi:10.1007/s00535-012-0667-z

Abstract

Background

Altered functions of dendritic cells (DCs) and/or increases of regulatory T cells (Tregs) are involved in the pathogenesis of chronic hepatitis C virus (HCV) infection. A tryptophan-catabolizing enzyme, indoleamine 2,3-dioxygenase (IDO), is reported to be an inducer of immune tolerance. Our aim was to clarify whether or not IDO is activated in chronic hepatitis C patients and its role in immune responses.

Methods

This study enrolled 176 patients with chronic HCV infection and 37 healthy volunteers. Serum kynurenine concentration was evaluated by high-performance liquid chromatography, and its correlation with clinical parameters was examined. Monocyte-derived DCs were prepared from the subjects and subsequently stimulated with a combination of lipopolysaccharide and interferon-gamma to induce functional IDO (defined as IDO-DCs). The phenotypes, kynurenine or cytokine production, and T-cell responses with IDO-DCs were compared between the patients and healthy volunteers.

Results

The serum kynurenine level in the patients was significantly higher than that in the healthy volunteers, and the level of serum kynurenine was positively correlated with the histological activity or fibrosis score. IDO activity in IDO-DCs from the patients was significantly higher than that in IDO-DCs from the volunteers. Furthermore, IDO-DCs from the patients induced more Tregs in vitro compared with those from the volunteers, and the frequency of induced Tregs by IDO-DCs was decreased with an IDO-specific inhibitor.

Conclusions

Systemic IDO activity is enhanced in chronic hepatitis C patients in correlation with the degree of liver inflammation and fibrosis. In response to inflammatory stimuli, DCs from the patients tend to induce Tregs, with some of this action being dependent on IDO.

Keywords

Hepatitis C virusDendritic cellRegulatory T cellIndoleamine 2,3-dioxygenase

Supplementary material

535_2012_667_MOESM1_ESM.pdf (144 kb)
Supplementary Figures (PDF 144 kb)

Copyright information

© Springer 2012