Rapid virological response is associated with increased pretreatment Th1 type cytokine production of Toll-like receptor 4 stimulated monocytes in HCV1 patients

Abstract

Aims: In chronic HCV hepatitis rapid viral decline over four weeks of IFN and ribavirin treatment is the best predictor of sustained virological response. As less is known of the immunologic basis of rapid virological response we compared the phenotypes and cytokine production of peripheral blood mononuclear cells of rapid, slow and non-responders before treatment initiation. Methods: Fifty patients with chronic HCV hepatitis before and at 1 and 3 months of PEG-IFN+ribavirin treatment were studied. The percentage of CD4, CD8, CD56, CD19, Treg, CD14 cells and TNF-alpha, IL-2, IL-6, IFN-gamma, IL-4, IL-10 production of LPS stimulated monocytes and PMA+ionomycine stimulated lymphocytes were determined by Flow Cytometry. Results: Baseline, LPS induced TLR4 activation of the monocytes induced significantly higher Th1 type cytokine production in rapid responders (n=14)(TNFa:3.53ng/ml, IL6:75.7ng/ml) compared to slow responders (n=17)(TNF-alpha:0,64ng/ml, IL-6:23.8ng/ml) and also to non-responders (n=19)(TNFa:0.58ng/ml, IL-6:18.9ng/ml). Rapid HCV RNA clearance was also associated with decreased Th2 type cytokine production of lymphocytes. IL-4 and IL-10 production of lymphoctes were significantly higher in slow responders (IL-4: 2.3ng/ml, IL-10: 0.85ng/ml) and non-responders (IL-4:1.94ng/ml, IL-10:0.62ng/ml) compared to rapid responders (IL-4:1.1ng/ml, IL-10:0.33ng/ml). TNFalpha production of monocytes was predictive for rapid virological response. While PEG-IFN and ribavirin treatment increased IL-2, IFN-gamma, TNF-alpha production in slow responders, it had no effect on non-responders. Conclusion: An elevated TNF-alpha and IL-6 production of TLR4 stimulated monocytes, increased IFN-gamma and diminished IL-4 and IL-10 production of peripheral blood lymphocytes were associated with rapid virological response. Determination of cytokine production may help identify patients more likely to respond to antiviral therapy as well as provide a rationale for the futher design and use of immunotherapeutic approaches.