Treatment with phosphodiester CpG-ODN ameliorates atopic dermatitis by enhancing TGF-β signaling

Abstract

Synthetic oligodeoxynucleotides (ODNs) containing unmethylated CpG phosphorothioate (PS CpG-ODN) are known to decrease IgE synthesis in Th2 allergy responses. Nonetheless, the therapeutic role of PS CpG-ODN is limited due to cytotoxicity. Therefore, we developed a phosphodiester (PO) form of CpG-ODN (46O) with reduced toxicity but effective against allergies. In this study, we first compared the toxicity of 46O with CpG-ODNs containing a PS backbone (1826S). We also investigated the therapeutic efficacy and mechanism of 46O injected intravenously in a mouse model of ovalbumin (OVA)-induced atopic dermatitis (AD). To elucidate the mechanism of 46O underlying the inhibition of IgE production, IgE- and TGF-β-associated molecules were evaluated in CD40/IL-4- or LPS/IL-4-stimulated B cells. Our data showed that the treatment with 46O was associated with a lower hematological toxicity compared with 1826S. In addition, injection with 46O reduced erythema, epidermal thickness, and suppressed IgE and IL-4 synthesis in mice with OVA-induced AD. Additionally, 46O induced TGF-β production in LPS/IL-4-stimulated B cells via inhibition of Smad7, which suppressed IgE synthesis via interaction between Id2 and E2A. These findings suggest that enhanced TGF-β signaling is an effective treatment for IgE-mediated allergic conditions, and 46O may be safe and effective for treating allergic diseases such as AD and asthma.

Mechanism of Th17 and Treg in Allergic Rhinitis

“…According to Park and others, TGF-β directly diminish serum IgE function by disrupting B cell maturation in atopic dermatitis, and indirectly reduce IgE expression by inhibiting mast cell response induced by IL-33 and STAT3 and ERK signalling pathways, which suppressed TNF-α production, and suppressing mast cell responses to IgE. Enhanced TGF-β signalling is associated with the anti-allergen effect of CpG-ODN, which induce Id2/E2A complexes in LPS/IL-4-stimulated B cells to down regulate IgE production and inhibit IgE class switch recombination [22]. Based on these studies, Treg cytokines inhibit inflammation in AR by regulating other interleukins and via signal transduction pathways, or by acting on T lymphocytes and B cells.…”