Lerat, H. (Hervé)

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    Improved dendritic cell-based immunization against hepatitis C virus using peptide inhibitors of interleukin 10
    (Wiley blackwell, 2011) Riezu-Boj, J.I. (José Ignacio); Echeverria, I. (Itziar); Diaz-Valdes, N. (Nancy); Borras-Cuesta, F. (Francisco); Larrea, E. (Esther); Lerat, H. (Hervé); Prieto, J. (Jesús); Llopiz, D. (Diana); Sarobe, P. (Pablo); Belsue, V. (Virginia); Lopez-Sagaseta, J. (Jacinto); Manterola, L. (Lorea); Pawlotsky, J.M. (Jean-Michel); Lasarte, J.J. (Juan José)
    The high levels of interleukin 10 (IL-10) present in chronic hepatitis C virus (HCV) infection have been suggested as responsible for the poor antiviral cellular immune responses found in these patients. To overcome the immunosuppressive effect of IL-10 on antigen-presenting cells such as dendritic cells (DCs), we developed peptide inhibitors of IL-10 to restore DC functions and concomitantly induce efficient antiviral immune responses. Two IL-10-binding peptides (p9 and p13) were selected using a phage-displayed library and their capacity to inhibit IL-10 was assessed in a bioassay and in STAT-3 (signal transducer and activator of transcription 3) phosphorylation experiments in vitro. In cultures of human leukocytes where HCV core protein induces the production of IL-10, p13 restored the ability of plasmacytoid DC to produce interferon alpha (IFN-α) after Toll-like receptor 9 (TLR9) stimulation. 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 immune responses by restoring the immunostimulatory capabilities of DC.