Improved dendritic cell-based immunization against hepatitis C virus using peptide inhibitors of interleukin 10

Abstract

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 antigenpresenting 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-a) 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-c 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. (HEPATOLOGY 2011;53:23-31)

Importance of IL-10 and IL-6 during chronic hepatitis c genotype-1 treatment and their relation with IL28B

“…Later, Brooks et al [28] performed in vivo experiments on infected mice and observed an association between falling IL-10 and viral clearance, and suggested that early neutralization of IL-10 would help prevent persistent infection. Recently, Diaz-Valdes et al [29] used peptide inhibitors of IL-10 (p9 and p13) in vitro, to restore dendritic cell functions and induce efficient antiviral immune responses. These authors suggested that IL-10 inhibitors might have important immunotherapeutic applications.…”

Elevation of plasma soluble human leukocyte antigen–G in patients with chronic hepatitis C virus infection

“…We found here that IL-10 and IFN-␥ were enhanced dramatically in the CHC patients. The high levels of IL-10 present in chronic HCV infection have been suggested as responsible for the poor antiviral cellular immune responses found in CHC patients, whereas IFN-␥ is a potent antiviral agent [41,42]. Despite their roles played in the progression of HCV infection, no correlation was established for both IL-10 and IFN-␥ with the expression of sHLA-G, indicating that an increased sHLA-G production may not induced by IL-10 and IFN-␥ in HCV infection.…”

Milk Derived Peptides with Immune Stimulating Antiviral Properties

“…At the present time, many peptides with immune regulating effects have been approved for clinical use against virus infection, such as Zadaxin, IM862, SCV-07 and so on [193]. Similarly, two peptide inhibitors of interleukin-10 may be applied to increase anti-hepatitis C virus immune response by restoring the immune stimulatory capabilities of dendritic cells, which have been suppressed by high levels of interleukin-10 [194]. Moreover, candidacidal activities of a synthetic peptide from human lactoferrin fraction 1-11 and 21-31 have been investigated for killing of multidrug-resistant pathogens [195][196][197][198][199].…”