Digestive and Liver Disease 43 (2011) 807–813 Contents lists available at ScienceDirect Digestive and Liver Disease j our nal ho me page: www.elsevier.com/locate/dld Liver, Pancreas and Biliary Tract Redistribution of regulatory T-cells across the evolving stages of chronic hepatitis C Silvia Ferri a,∗ , Claudine Lalanne a , Giulia Lanzoni a , Mirna Bassi b , Sofia Asioli c , Valentina Cipriano a , Georgios Pappas a , Paolo Muratori a , Marco Lenzi a , Luigi Muratori a a Department of Clinical Medicine, University of Bologna, Bologna, Italy b Department of Clinical Pathology, S. Orsola-Malpighi Hospital, Bologna, Italy c Department of Biomedical Sciences and Human Oncology, University of Turin, Turin, Italy a r t i c l e i n f o Article history: Received 14 January 2011 Accepted 28 April 2011 Keywords: Chronic HCV-related liver disease Decompensated cirrhosis MELD score Regulatory T-cells a b s t r a c t Background: Hepatitis C virus infection frequently leads to chronic hepatitis, possibly evolving to end- stage liver disease and hepatocellular carcinoma. Regulatory T cells can affect antiviral immune response thus influencing the outcome of the disease. Aim: To determine numeric and functional distribution of regulatory T cells expressing CD4+CD25hiFoxp3+ (T-regs) during the different stages of hepatitis C virus-related liver disease. Methods: 90 hepatitis C viraemic patients and 50 healthy controls were included. Surface and intracellular (Foxp3) T-reg markers were evaluated by flow cytometry. Target cell proliferation and interferon-gamma production were evaluated in 37 HCV patients. In 16 cases intrahepatic distribution of Foxp3 by immuno- histochemistry was assessed. Results: T-regs were increased in hepatitis C virus infected patients and correlated inversely with aminotransferases and directly with MELD score and disease duration. A preserved inhibitory ability of interferon-gamma production was distinctive of patients with normal aminotransferases. Circulating T-regs did not correlate with intrahepatic distribution of Foxp3. Conclusions: In chronic hepatitis C, selective expansion of peripheral T-regs in patients with normal aminotransferases and advanced disease suggests that, though a continual low level inflammation does not prevent liver disease progression, once cirrhosis has developed it may represent an attempt to prevent immuno-mediated decompensation. © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. 1. Introduction Hepatitis C virus (HCV) infection affects some 180 million indi- viduals worldwide and in the vast majority of cases it leads to chronic liver disease; a proportion of these patients are expected to develop, over 2–4 decades, progressive hepatic fibrosis possibly evolving in cirrhosis and liver failure, or hepatocellular carcinoma [1,2]. Different host factors such as older age, male gender, African- American ethnicity, alcoholism, smoking, co-infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) and co- morbidity with steatosis and metabolic syndrome are responsible for a quicker evolution of the disease; whereas viral features, such as HCV viral load and genotypes, are not universally associated with ∗ Corresponding author at: Department of Clinical Medicine, University of Bologna, Via Massarenti 9, 40138 Bologna, Italy. Tel.: +39 051 6363865; fax: +39 051 6363631. E-mail address: silvia.ferri9@unibo.it (S. Ferri). liver disease progression [3]. Immunological factors play a promi- nent role in controlling HCV infection, whose eradication requires a coordinated inter-play between innate and adaptive immunity. A vigorous and multi-specific immune response, involving CD4 and CD8 T lymphocytes, NK cells, B lymphocytes and dendritic cells, is associated with pathogen clearance and disease resolution. In contrast, a narrowly focused and/or delayed response of T and B lymphocytes seems to favour the development of chronic HCV infection [4], but, limiting liver damage, may ultimately guarantee host survival [5]. In the last decade, new classes of T lymphocytes with regula- tory properties capable of suppressing effector T cells have been described. Amongst them, the best known are the so-called T- regs, naturally occurring CD4+CD25+T cells expressing CD25 at high levels (CD25hi), surface markers such as CD45RO and CD62L and the forkhead/winged helix transcription factor Foxp3 [6–9]. CD4+CD25hiFoxp3+ T cells suppress the activities of effector T cells both directly and indirectly via down-regulation of antigen- presenting cells by reducing their histo-compatibility molecule class II (MHC-II) and costimulatory protein expression, alter- 1590-8658/$36.00 © 2011 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved. doi:10.1016/j.dld.2011.04.020