EXPRESSION PATTERNS OF CHEMOKINE RECEPTORS CXCR3 AND CCR6, AND THEIR LIGANDS IN PERIPHERAL BLOOD OF PATIENTS WITH CHRONIC HEPATITIS C DURING ANTIVIRAL THERAPY USING PEGYLATED INTERFERONS

Abstract

The work presents data on forty-one patients with chronic hepatitis C (HCV, genotype 1), at different liver fibrosis stages. The studies were performed in the course of interferon-containing treatment regimens, i.e., pegylated interferon combined with ribavirin and pegylated interferon; ribavirin together with NS3/4A inhibitor of HCV serine protease. Concentrations of cytokines/chemokines (TNFα, CCL2/MCP-1, CCL20/MIP-3α, CXCL9/MIG, CXCL10/IP-10, CXCL11/ITAC) were measured in blood plasma samples, using xMAP multiplex analysis. Flow cytometry studies were also performed in order to reveal cells with CCR6 and CXCR3 receptors in lymphocyte populations. The obtained results were analyzed using a statistical program package R. Results: 36 out of 41 patients achieved virological response, while 5 patients did not respond to the therapy. The responders were split into two groups, as follows: (1) liver fibrosis-free; (2) patients with fibrosis stages 1, 2 and 3. In the group of fibrosis-free patients, the decrease of CXCL11/ITAC concentration and the increase of TNFαwere observed, as well as increase of CTL CXCR3+ content by the 12th week of therapy and an increase of NK CXCR3+ by the end of treatment. In addition, this group exhibited a decrease in the CXCR3+ B lymphocyte contents at this timepoint. Concentrations of CCL2/MCP-1 during treatment were increased in the patients with different stages of liver fibrosis, as compared to baseline. By the end of therapy, an increase in the relative content of NK CXCR3+and TNK CCR6+ was also detected. The study confirmed a potential role of cytokines/chemokines TNFα, CCL2/MCP-1 and CXCL11/ITAC in activation of the cell-mediated immunity and elimination of the hepatitis C virus from the body. The results indicate that activation of T cellmediated immunity in both groups of the patients and reduction of B cells with CXCR3 receptor in the patients of first group is a positive prognostic factor showing efficiency of interferon therapy. Two of studied cytokines/ chemokines (TNFαand CCL20/MIP3α) differed in the groups of responders and non-responders at the start of therapy. Statistical evaluation of pre-treatment results has shown a tendency for differing concentration of TNFα, and CCL20/MIP3αamounts were significantly different for the patients of these groups. The plasma concentrations of CCL20/MIP3αin non-responders were > 4-fold higher than in responders to the therapy. Hence, the present study allowed us to propose the chemokine CCL20/MIP3α as a potential predictor of treatment outcomes in HCV infection.

Keywords

• hepatitis c
• antiviral therapy
• chemokines
• fibrosis
• mip-3α
• tnfα
• ctl cxcr3+
• nk cxcr3+
• therapy outcome