BACKGROUND AND AIM: The immunological mechanism by which ribavirin (RBV) polarizes the T-helper (Th) 1/2 balance toward Th1 predominancy is not fully understood. We therefore examined whether RBV affects costimulatory signaling, which is known to be essential for regulating the Th1/2 balance. METHODS: The expression of costimulatory molecules and their ligands, and levels of various cytokines, released from CD4(+) T cells obtained from healthy individuals or patients with chronic hepatitis C virus (HCV) infection were analyzed. RESULTS: In CD4(+) T cells, RBV selectively downmodulates the expression of inducible costimulator (ICOS), a ligand for B7-H2 on dendritic cells, which mainly differentiates Th0 into Th2 cells. Moreover, the levels of interleukin-10 (IL-10) released from RBV-stimulated CD4(+) T cells also decreased, indicating that the downmodulation of ICOS induced by RBV might be correlated with the decrease in IL-10 released from Th cells, leading to the inhibition of Th2 activity. An analysis of the association between ICOS kinetics and hepatitis C virus (HCV) elimination in hepatitis C patients receiving combined pegylated interferon and RBV indicated that HCV elimination tended to occur more frequently in patients showing ICOS downmodulation with RBV treatment. A decrease in IL-10 production by CD4(+) T cells was also observed in association with ICOS downregulation in patients who succeeded in HCV elimination. CONCLUSIONS: The downmodulation of ICOS in correlation with a reduction in IL-10 produced by CD4(+) T cells is possibly the immunological mechanism of action of RBV, which polarizes the Th1/2 balance toward a Th1 cytokine profile, thus contributing to the elimination of cells chronically infected with HCV.
BACKGROUND AND AIM: The immunological mechanism by which ribavirin (RBV) polarizes the T-helper (Th) 1/2 balance toward Th1 predominancy is not fully understood. We therefore examined whether RBV affects costimulatory signaling, which is known to be essential for regulating the Th1/2 balance. METHODS: The expression of costimulatory molecules and their ligands, and levels of various cytokines, released from CD4(+) T cells obtained from healthy individuals or patients with chronic hepatitis C virus (HCV) infection were analyzed. RESULTS: In CD4(+) T cells, RBV selectively downmodulates the expression of inducible costimulator (ICOS), a ligand for B7-H2 on dendritic cells, which mainly differentiates Th0 into Th2 cells. Moreover, the levels of interleukin-10 (IL-10) released from RBV-stimulated CD4(+) T cells also decreased, indicating that the downmodulation of ICOS induced by RBV might be correlated with the decrease in IL-10 released from Th cells, leading to the inhibition of Th2 activity. An analysis of the association between ICOS kinetics and hepatitis C virus (HCV) elimination in hepatitis C patients receiving combined pegylated interferon and RBV indicated that HCV elimination tended to occur more frequently in patients showing ICOS downmodulation with RBV treatment. A decrease in IL-10 production by CD4(+) T cells was also observed in association with ICOS downregulation in patients who succeeded in HCV elimination. CONCLUSIONS: The downmodulation of ICOS in correlation with a reduction in IL-10 produced by CD4(+) T cells is possibly the immunological mechanism of action of RBV, which polarizes the Th1/2 balance toward a Th1 cytokine profile, thus contributing to the elimination of cells chronically infected with HCV.