Treatment with ribavirin and interferon-alpha reduces interferon-gamma expression in patients with chronic hepatitis C

Abstract

Recent studies in vitro and in animals have suggested that ribavirin may potentiate the antihepatitis C virus (HCV) activity of interferon-alpha (IFN-alpha) by up-modulating the production of T cell-derived cytokines, such as interleukin (IL)-2 and IFN-gamma, which play a key role in the cellular immune response against HCV. To study the immune-modulatory mechanisms of ribavirin further, cytokine production by activated T cells and circulating cytokine levels were studied by FACS analysis and ELISA testing in 25 patients with chronic hepatitis C unresponsive to IFN-alpha, before and after treatment with either ribavirin plus IFN-alpha or IFN-alpha alone. After 16 weeks of treatment, both the expression of IFN-gamma by activated T cells and the blood levels of IFN-gamma, were significantly reduced with respect to pretreatment values in patients treated with ribavirin and IFN-alpha but not in those undergoing treatment with IFN-alpha alone. The expression of IFN-gamma was significantly lower in patients that gained normal ALT levels with respect to those that did not. No modification of the expression of IL-2, IL-4 and IL-10 was found before and after treatment in either group of patients. In conclusion, the results of this study do not support up-modulation of IFN-gamma and IL-2 production as the mechanism by which ribavirin potentiates IFN-alpha anti HCV activity. In addition, our findings suggest that ribavirin may exert an anti-inflammatory effect and may help reducing IFN-gamma-driven T cell activation and liver damage.

Fig. 1

Cytokine production by activated PBMC from patients before (□) and after 4 months of treatment (▪) with ribavirin and IFN-α or IFN-α alone. (a) IFN-γ; (b) IL-2; (c) IL-4; (d) IL-10. Cytokine production was determined by ELISA testing of supernatants from unfractionated PBMC. Bars represent S.D.

Fig. 2

Decrease of IFN-γ expression studied on a single patient basis after 4 months of treatment with ribavirin and IFN-α with respect to pretreatment values. (a) Patients that did not gain normal ALT values after 4 months of treatment. (b) Patients with normal ALT values after 4 month of treatment. The percentage of IFN-γ-producing cells was determined by FACS (▪) as described in the legend of Table 2. IFN-γ production by activated PBMC was determined by ELISA (□) testing of supernatants from unfractionated PBMC. The percenc reduction of IFN-γ production was calculated as follows: 100-(baseline percentage IFN-γ expression/4 months percentage IFN-γ expression).