A class C CpG toll‐like receptor 9 agonist successfully induces robust interferon‐alpha production by plasmacytoid dendritic cells from patients chronically infected with hepatitis C

Abstract

Immunomodulators that induce local endogenous interferon-alpha (IFN-α) production by plasmacytoid dendritic cells (pDCs) may offer new strategies for the treatment of patients chronically infected with the hepatitis C virus (HCV). However, such an approach may be compromised if reports are true that IFN-α production by pDCs from patients with chronic HCV (cHCV) is profoundly impaired. To address the question of pDC dysfunction in cHCV more definitively, in the present study a panel of four prototypic synthetic agonists of toll-like receptor 7 (TLR7) or TLR9 were administered in vitro to pDCs purified from cHCV patients and from normal uninfected donors and their responses compared in terms of not only IFN-α production but also the global expression of other cytokines and phenotypic maturation. Plasmacytoid DCs from uninfected donors produced substantial levels of IFN-α in response to three of the four agonists and yet only one TLR9 agonist, a class C CpG oligodeoxynucleotide (ODN), induced robust IFN-α production by pDCs from cHCV patients. Proinflammatory cytokine production and phenotypic maturation in response to all four agonists was equivalent in infected and uninfected pDCs. These data point to a profound but selective defect in IFN-α production by pDCs from cHCV donors. Nonetheless, a class C CpG ODN successfully induced robust IFN-α production, suggesting that this class of TLR9 agonist may have utility as a future immunotherapeutic for the treatment of chronic HCV infection.

Dendritic cells in hepatitis C infection: can they (help) win the battle?

“…Baseline chemotaxis of PDCs to CXCL12 and CXCL10 is low and is predictive of failed antiviral response, while correlating with the histological activity index inflammation score [39]. All these defects can be attributed to the presence of HCV RNA in PDCs [55,64], and by the normalization of PDC functions in patients who have cleared the virus upon treatment with antiviral therapy [48,61,62]. Surprisingly PDCs exhibit little susceptibility to viral entry when delivered forcefully or by simple incubation and they are not susceptible to pseudotype VSV-E1E2 entry [65].…”

“…The allostimulatory capacity of PDCs from patients is reduced, as compared to controls, and HCV-PDCs induce IL-10 production in T cells [56]. However, PDCs of HCV patients have distinct particularities in cytokine profile [54,62]; they are also on the low side in responding to influenza A and are high responders to poly (I:C) compared to controls [50,63].…”

Prophylactic and therapeutic implications of toll‐like receptor ligands

“…The impaired capacity of plasmacytoid DCs to produce IFN‐α upon in vitro stimulation with TLR7 and TLR9 agonists has been reported in patients with chronic HCV infection. Nonetheless, a class C CpG ODN TLR9 agonist successfully induced robust IFN‐α production, rendering it a plausible candidate for the treatment of chronic HCV infection …”

“…Nonetheless, a class C CpG ODN TLR9 agonist successfully induced robust IFN-a production, rendering it a plausible candidate for the treatment of chronic HCV infection. 130 At present, AldaraTM has been approved for therapeutic use in external genital warts caused by human papillomavirus. 113 The most frequently reported adverse events were mild to moderate local skin and application site reactions.…”

The Incidence and Significance of Pattern-Recognition Receptors in Chronic Viral Hepatitis Types B and C in Man

“…Attention was focused on TLR agonists, both natural and synthetic, because these agents are able to raise TLR activity. For example, it was found recently that synthetic class C CpG ODN agonists of TLR9 induced robust IFN-a production in vitro by pDCs from chronic HCV patients (Libri et al 2009). This was of interest because, as shown earlier, viral products act antagonistically toward type 1 IFN synthesis.…”