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

  • Koyo Higashitani
  • Tatsuya Kanto
  • Shoko Kuroda
  • Sachiyo Yoshio
  • Tokuhiro Matsubara
  • Naruyasu Kakita
  • Tsugiko Oze
  • Masanori Miyazaki
  • Mitsuru Sakakibara
  • Naoki Hiramatsu
  • Eiji Mita
  • Yasuharu Imai
  • Akinori Kasahara
  • Alato Okuno
  • Osamu Takikawa
  • Norio Hayashi
  • Tetsuo Takehara
Original Article—Liver, Pancreas, and Biliary Tract

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 virus Dendritic cell Regulatory T cell Indoleamine 2,3-dioxygenase 

Supplementary material

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

Copyright information

© Springer 2012

Authors and Affiliations

  • Koyo Higashitani
    • 1
  • Tatsuya Kanto
    • 1
  • Shoko Kuroda
    • 1
  • Sachiyo Yoshio
    • 1
  • Tokuhiro Matsubara
    • 1
  • Naruyasu Kakita
    • 1
  • Tsugiko Oze
    • 1
  • Masanori Miyazaki
    • 1
  • Mitsuru Sakakibara
    • 2
  • Naoki Hiramatsu
    • 1
  • Eiji Mita
    • 3
  • Yasuharu Imai
    • 4
  • Akinori Kasahara
    • 5
  • Alato Okuno
    • 6
  • Osamu Takikawa
    • 6
  • Norio Hayashi
    • 7
  • Tetsuo Takehara
    • 1
  1. 1.Department of Gastroenterology and HepatologyOsaka University Graduate School of MedicineSuitaJapan
  2. 2.Osaka Medical Center for Cancer and Cardiovascular DiseasesOsakaJapan
  3. 3.National Hospital Organization Osaka National HospitalOsakaJapan
  4. 4.Ikeda Municipal HospitalIkedaJapan
  5. 5.Department of General MedicineOsaka University HospitalSuitaJapan
  6. 6.Laboratory of Radiation SafetyNational Center for Geriatrics and GerontologyObuJapan
  7. 7.Kansai Rosai HospitalHyogoJapan

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