Synergic Effects of CD40 and CD86 Silencing in Dendritic Cells on the Control of Allergic Diseases

BACKGROUND:We previously reported that siRNA-induced CD40-silenced dendritic cells (DCs) inhibit allergic responses and symptoms. However, more potent therapies are needed. To our knowledge, synergic effects of gene silencing in DCs by ≥2 siRNAs have not been reported to control allergic diseases. Therefore, we investigated the synergistic effects of the silencing of CD40 and CD86 in DCs on allergic responses. METHODS:Mice were treated with CD40/CD86-silenced DCs, which were transfected with CD40/CD86 siRNAs and pulsed with ovalbumin (OVA) antigen. The effects of these DCs on allergic symptoms and allergic responses were estimated. RESULTS:The administration of CD40/CD86-silenced OVA-pulsed DCs significantly inhibited the number of sneezes and nasal rubbing movements, the number of eosinophils in the nasal mucosa, and the level of OVA-specific IgE when compared with those for CD40- or CD86-silenced OVA-pulsed DCs alone (p < 0.01). These inhibitory effects were detected before sensitization as well as after the establishment of allergic rhinitis. CD40/CD86-silenced OVA-pulsed DCs did not inhibit KLH-induced allergies. Foxp3 gene expression was significantly upregulated in CD40-silenced DCs compared to in CD86-silenced DCs (p < 0.01). IL-4 production by T cells was suppressed more substantially when using CD86-silenced DCs than with CD40-silenced DCs (p < 0.01). CONCLUSIONS:These results indicate, for the first time, that siRNA-induced CD40/CD86-silenced antigen-specific DCs have greater inhibitory effects against allergic responses than those of CD40- or CD86-silenced antigen-specific DCs alone. This study also suggests that the synergic effects of gene silencing in DCs by ≥2 siRNAs are useful for the control of allergic diseases. Thus, owing to the synergistic effects, CD40 and CD86 silencing has the potential to substantially improve the treatment of allergic diseases.