Analysis of peripheral blood dendritic cells as a non-invasive tool in the follow-up of patients with chronic hepatitis C

Abstract

Hepatitis C virus (HCV) has a high propensity to establish chronic infections. Failure of HCV-infected individuals to activate effective antiviral immune responses is at least in part related to HCV-induced impairment of dendritic cells (DCs) that play a central role in activating T cell responses. Although the impact of HCV on DC phenotype and function is likely to be more prominent in the liver, major HCV-induced alterations are detectable in peripheral blood DCs (pbDCs) that represent the most accessible source of DCs. These alterations include numerical reduction, impaired production of inflammatory cytokines and increased production of immunosuppressive IL10. These changes in DCs are relevant to our understanding the immune mechanisms underlying the propensity of HCV to establish persistent infection. Importantly, the non-invasive accessibility of pbDCs renders the analysis of these cells a convenient procedure that can be serially repeated in patient follow-up. Accordingly, the study of pbDCs in HCV-infected patients during conventional treatment with pegylated interferon and ribavirin indicated that restoration of normal plasmacytoid DC count may represent an additional mechanism contributing to the efficacy of the dual therapy. It also identified the pre-treatment levels of plasmacytoid DCs and IL10 as putative predictors of response to therapy. Treatment of chronic HCV infection is changing, as new generation direct-acting antiviral agents will soon be available for use in interferon-free therapeutic strategies. The phenotypic and functional analysis of pbDCs in this novel therapeutic setting will provide a valuable tool for investigating mechanisms underlying treatment efficacy and for identifying predictors of treatment response.

Keywords: Cytokines; Hepatitis C virus; Peg-interferon; Peripheral blood dendritic cells; Ribavirin.

Figure 1

Summary of the hepatitis C virus-associated alterations of dendritic cells detectable in the peripheral blood. Patients with chronic hepatitis C undergo changes in the number and function of both myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs) that may be relevant to the pathogenesis of chronic HCV infection. In particular, several Authors demonstrated that pDCs, which are specialized in antiviral immune responses, are decreased in HCV-infected patients and are endowed with a reduced ability to produce interferon (IFN). mDCs, that contribute to the activation of cellular immunity through the production of interleukin (IL)12, are decreased as well and characterized by reduced production of IL12 and increased production of the immunosuppressive cytokine IL10. These last functional defects are shared by monocyte-derived DCs that are also endowed with decreased ability to activate T cells. All references are reported in the text.

Figure 2

Effects of dual therapy with pegylated interferon and ribavirin on peripheral blood dendritic cells. The treatment induced a rapid, progressive and persistent increase of plasmacytoid dendritic cells (pDCs) in sustained virological response (SVR) but not in non-SVR patients. The frequency of pDCs was higher in SVR than non-SVR patients at all the time points. pegIFN and RBV treatment also induced a transient increase of peripheral blood DC production of interleukin (IL)12, that was observed after 1 mo of treatment but decreased thereafter, and that was more pronounced in SVR than non-SVR patients. IL10 production showed a similar trend and tended to be higher in non-SVR patients. ^aP < 0.05 and ^bP < 0.01, respectively, any time vs t0 within each group, as assessed by Wilcoxon signed rank test; ^cP < 0.05, SVR vs non-SVR, as assessed by Mann-Whitney test. t0: Before treatment; t1: After 1 mo of treatment; t2: At the end of treatment; t3: 6 mo after treatment completion.