High concentrations of CpG-B ODNs induce a novel IFNαβ-specific inhibitory pathway in dendritic cells (89.9)

Abstract CpG oligodeoxynucleotides (ODNs) signal through TLR9 to induce type-I IFN (IFNαβ) and other immunomodulatory responses (i.e., TNF, IL-12p40, and MHC-I, etc.) by antigen presenting cells. CpG ODNs are currently in preclinical and clinical studies as vaccine adjuvants and therapies for allergies and cancers. Caveats to CpG ODN therapies are the possible provocation of autoimmune diseases such as systemic lupus erythematosis, which may be exacerbated by the induction of CpG-induced IFNαβ. Thus, further studies are needed to examine CpG induction of IFNαβ and to develop agents to inhibit the induction of IFNαβ by CpG ODNs. These studies address a mechanism for inhibiting induction of IFNαβ that could potentially offer an approach for therapeutic inhibition of IFNαβ expression in vivo. Our data suggest that high concentrations of CpG-B ODNs (H/CpG-B) induce an IFNαβ specific inhibitory mechanism as early as 3 h and sustained inhibition as long as 48 h, without similarly affecting TNF and IL-12p40 levels. Additionally, H/CpG-B inhibits MyD88-dependent (CpG-A ODNs) and -independent (Sendai virus) induction of IFNαβ. However, H/CpG-B fails to inhibit IFNαβ expression following induction with recombinant IFNαA protein, suggesting that H/CpG-B IFNαβ inhibition is upstream of the IFNαβ receptor and possibly due to specific obstruction of early type-I IFN induction (IFNα4/β). These data demonstrate a novel IFNαβ specific inhibitory mechanism induced by stimulation of DCs in vitro with H/CpG-B ODNs.