In this line, in vitro neutralization of IL-10 in PBMC from HCV-infected patients recovered the activity of low-responsive T-cells.3, 31 Although the mechanism responsible for this recovery is not characterized, restoration of functional properties of DC and concomitantly of T-cells might explain these results. Thus, IL-10 inhibition in HCV infection might enhance T-cell immunity facilitating viral clearance. An important finding obtained using peptide inhibitors of IL-10 is that they not only inhibit IL-10
released in response to HCV proteins, but also IL-10 induced by maturation stimuli. Indeed, activation of mDC with CD40L in the presence of p9 enhanced IL-12 production. Thus, we hypothesized that inhibiting an endogenous brake, like IL-10, synthesized upon CD40L stimulation, may be useful to improve Selleckchem LY294002 the functional properties of DC. This buy Ibrutinib strategy may increase
the immunogenicity of DC, leading to higher efficacy of DC-based vaccination procedures. Using human MoDC (DC population commonly used in vaccination), we found that inhibition of endogenous IL-10 with p13 enhanced their immunogenicity in vitro, increasing lymphocyte proliferation and IFN-γ production, the prototypical Th1 cytokine. Similar results were obtained with murine DC, in agreement with the ability of these peptides to bind and inhibit murine IL-10, which has more than 70% homology with hIL-10. More important, immunization with p13-treated DC in different antigenic models, including mice expressing a secretable version of HCV core as well as transgenic mice expressing the full HCV polyprotein, led to the induction of stronger anti-NS3 T-cell responses, measured as IFN-γ production. Thus, these peptides may have important applications in HCV infection not only in vivo, to inhibit IL-10, thus modulating immune responses, but also ex vivo, in clinical protocols based on the use of DC loaded with HCV antigens for further
administration in therapeutic vaccination. An interesting result regarding the activity of p13 and p9 is their selective effect on their ability ADAMTS5 to restore cytokine production by different DC populations. We do not have a clear explanation, but it might be speculated that these DC populations and their functions have a different sensitivity to be inhibited by IL-10. This might be related to differences in the site of binding to IL-10 by p9 and p13, resulting in specific effects on both types of DC populations. Similarly, binding of the anti-IL-10 antibody to another site on the cytokine may also explain differences in its effect. Finally, because IL-10 plays an immunosuppressive role32 in other diseases (infections by HBV, human immunodeficiency virus [HIV], Epstein-Barr virus [EBV], or cancer), we believe that these peptides might be also useful in these settings.