Studies of methylated CpG ODN from Bifidobacterium longum subsp. infantis in a murine model: Implications for treatment of human allergic disease.

Abstract

Background: Allergen immunotherapy (AIT) is currently the most effective immunologic form of treatment for patients with atopic allergic diseases commonly used by allergist/immunologists to reduce allergic symptoms by gradually desensitizing the immune system to specific allergens. Currently, the primary mechanism of AIT emphasizes the crucial role of immune regulation, which involves a shift from a T-helper type 2 (Th2) cell response, which promotes allergy, to a T-regulatory (Treg) cell population, which inhibits the allergic inflammatory response through the production of immunosuppressive cytokines interleukin 10 and transforming growth factor β, which play pivotal roles in suppressing the allergic reaction. In a series of previous in vitro and in vivo experiments, we have demonstrated the capacity of synthetic methylated cytosine-phosphate-guanine (CpG) oligodeoxynucleotide (ODN) moieties as well as methylated genomic DNA ODN motifs from Bifidobacterium longum subspecies infantis to activate Treg cell differentiation in contrast to the unmethylated ODN moiety, which promotes proinflammatory responses driven by Th17-mediated responses. Objective: The purpose of the present study was to continue exploring the reciprocally related effects of methylated and unmethylated forms of DNA motifs from B. longum subspecies infantis on inflammation, specifically focusing on evaluating their capacity to alleviate allergic symptoms in a murine allergic disease model. Results: We show that methylated CpG moieties (ODNA) inhibit inflammation by stimulating Treg cells whereas unmethylated CpG moieties (ODNB) promote inflammation through Th1/Th17 pathways. Conclusion: Analysis of our data confirms and extends our previous research on the mechanisms by which methylated and unmethylated forms of DNA motifs influence inflammation. Specifically, the findings demonstrate that methylated CpG moiety (OVA + ODNA) inhibits inflammation by stimulating Treg cells, whereas unmethylated CpG moiety (OVA + ODNB) promotes inflammation through Th1/Th17 pathways. Consequently, these effects were shown to alleviate or to exacerbate allergic symptoms in a murine model of allergic disease. These results set the stage for future clinical trials and studies in humans to explore the therapeutic potential of targeting CpG motifs in the treatment of allergic diseases.