Similarly, when myeloid DCs were stimulated with CD40L in the pre

Similarly, when myeloid DCs were stimulated with CD40L in the presence of HCV core, p9 enhanced IL-12 production by inhibiting HCV core-induced as well as CD40L-induced IL-10. Moreover, in vitro, p13 potentiated the effect of maturation stimuli on human and murine DC, increasing their IL-12 production and stimulatory activity, which resulted in enhanced proliferation and IFN-γ production

by responding T-cells. Finally, immunization with p13-treated murine DC induced stronger anti-HCV T-cell responses not only in wildtype mice but also in HCV transgenic mice and in mice transiently expressing HCV core in the liver. Conclusion: These results suggest that IL-10 inhibiting peptides may have important applications to enhance anti-HCV XL765 concentration immune responses by restoring the immunostimulatory capabilities of DC. (HEPATOLOGY 2011.) Chronic infection caused by hepatitis C virus (HCV) is characterized by low or nil antiviral T-cell responses, whereas viral clearance is associated with strong and multispecific T-cell responses.1 Among other mechanisms, production of immunosuppressive

cytokines such as interleukin 10 (IL-10)2, 3 has been postulated as responsible for this lack of efficient immunity. IL-10 is a pleiotropic cytokine traditionally considered as immunosuppressive and antiinflammatory, produced by many cell types (reviewed4), which exerts its effects by inhibiting macrophage and dendritic cell this website (DC) functions. In chronic HCV infection, patients have high serum levels of IL-10,5, 6 associated with incomplete responses to interferon IFN therapy.7 Interestingly,

these levels decline after successful treatment.6 IL-10 is produced in these patients by antigen-stimulated CD4 and CD8 T-cells, regulatory T-cells,3, 8, 9 and DC10-12 which in turn activate IL-10-producing T-cells.13In vitro experiments have demonstrated that some HCV proteins interacting with monocytes induce the production of IL-10.14, 15 Due to its antiinflammatory properties, IL-10 has been used therapeutically in HCV patients with liver fibrosis.16 Although administration of IL-10 decreased hepatic inflammation and fibrosis, HCV RNA levels increased, and antiviral CD4 and CD8 T-cells shifted from a Th1 to a Th2 cytokine profile. All these data suggest that overexpression of IL-10 in chronic HCV infection may contribute to the lack of efficient antiviral T-cell responses. Indeed, IL-10 is a key factor in determining viral clearance versus chronic infection in the LCMV murine model, and its inhibition converted a chronic into an acute infection, which could be controlled by the immune response.17, 18 Thus, for chronic HCV infection, inhibition of IL-10 would potentially enhance the efficacy of antiviral responses and, ultimately, lead to viral clearance.

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