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Allergen Immunotherapy in a Mouse Model of Allergic Asthma: Role for IL-10 and TGF-

1 ,25-Dihydroxyvitamin D3 (1,25(OH)2D3), a potent inhibitor of NFB expression, can prevent the maturation of dendritic cells in vitro leading to tolerogenic dendritic cells with increased potential to induce regulatory T cells. Herein, we investigated whether the combination of allergen immunotherapy with 1,25(OH)2D3 potentiates the suppressive effects of immunotherapy and whether the immunoregulatory cytokines IL-10 and TGFare involved in the effector phase. OVA-sensitized and challenged BALB/c mice displayed airway hyperresponsiveness (AHR) and increased serum OVA-specific IgE levels, bronchoalveolar lavage eosinophilia, and Th2 cytokine levels. In this model, the dose response of allergen immunotherapy 10 days before OVA inhalation challenge shows strong suppression of asthma manifestations at 1 mg of OVA, but partial suppression of bronchoalveolar lavage eosinophilia, IgE up-regulation, and no reduction of AHR at 100 g. Interestingly, coadministration of 10 ng of 1,25(OH)2D3 with 100 g of OVA immunotherapy significantly inhibited AHR and potentiated the reduction of serum OVA-specific IgE levels, airway eosinophilia, and Th2-related cytokines concomitant with increased IL-10 levels in lung tissues and TGFand OVA-specific IgA levels in serum. Similar effects on suboptimal immunotherapy were observed by inhibition of the NFB pathway using the selective I B kinase 2 inhibitor PS-1145. The suppressive effects of this combined immunotherapy were partially reversed by treatment with mAb to either IL-10R or TGFbefore OVA inhalation challenge but completely abrogated when both Abs were given. These data demonstrate that 1,25(OH)2D3 potentiates the efficacy of immunotherapy and that the regulatory cytokines IL-10 and TGFplay a crucial role in the effector phase of this mouse model. The Journal of Immunology, 2008, 180: 5211–5221.