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.
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 Cpatients 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 Cpatients 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.
Authors: Esther Larrea; José I Riezu-Boj; Lucía Gil-Guerrero; Noelia Casares; Rafael Aldabe; Pablo Sarobe; María P Civeira; Jonathan L Heeney; Christine Rollier; Babs Verstrepen; Takaji Wakita; Francisco Borrás-Cuesta; Juan J Lasarte; Jesús Prieto Journal: J Virol Date: 2007-01-17 Impact factor: 5.103
Authors: David H Munn; Madhav D Sharma; Babak Baban; Heather P Harding; Yuhong Zhang; David Ron; Andrew L Mellor Journal: Immunity Date: 2005-05 Impact factor: 31.745
Authors: D H Munn; M Zhou; J T Attwood; I Bondarev; S J Conway; B Marshall; C Brown; A L Mellor Journal: Science Date: 1998-08-21 Impact factor: 47.728
Authors: David H Munn; Madhav D Sharma; Jeffrey R Lee; Kanchan G Jhaver; Theodore S Johnson; Derin B Keskin; Brendan Marshall; Phillip Chandler; Scott J Antonia; Russell Burgess; Craig L Slingluff; Andrew L Mellor Journal: Science Date: 2002-09-13 Impact factor: 47.728
Authors: Catherine Uyttenhove; Luc Pilotte; Ivan Théate; Vincent Stroobant; Didier Colau; Nicolas Parmentier; Thierry Boon; Benoît J Van den Eynde Journal: Nat Med Date: 2003-09-21 Impact factor: 53.440
Authors: Heinz Zoller; Annina Jenal; Albert F Staettermayer; Sebastian Schroecksnadel; Peter Ferenci; Dietmar Fuchs Journal: Pharmaceuticals (Basel) Date: 2015-06-18
Authors: Deepak Mittal; Andrew J Kassianos; Lee S Tran; Anne-Sophie Bergot; Christine Gosmann; Janin Hofmann; Antje Blumenthal; Graham R Leggatt; Ian H Frazer Journal: J Invest Dermatol Date: 2013-05-07 Impact factor: 8.551