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.
Immunomodulators that induce local endogenous interferon-alpha (IFN-alpha) 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-alpha 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-alpha production but also the global expression of other cytokines and phenotypic maturation. Plasmacytoid DCs from uninfected donors produced substantial levels of IFN-alpha in response to three of the four agonists and yet only one TLR9 agonist, a class C CpG oligodeoxynucleotide (ODN), induced robust IFN-alpha 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-alpha production by pDCs from cHCV donors. Nonetheless, a class C CpG ODN successfully induced robust IFN-alpha production, suggesting that this class of TLR9 agonist may have utility as a future immunotherapeutic for the treatment of chronic HCV infection.
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iQur Ltd, Southampton General Hospital, Southampton, UK.
Barker
S J
SJ
Rosenberg
W M C
WM
Semper
A E
AE
D000328:Adult; D000368:Aged; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D005260:Female; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D016898:Interferon-alpha / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D051199:Toll-Like Receptor 7 / Q000819:agonists; D051217:Toll-Like Receptor 9 / Q000819:agonists*; D055815:Young Adult
C408982:CPG-oligonucleotide; D007155:Immunologic Factors; D016898:Interferon-alpha; D009838:Oligodeoxyribonucleotides; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9