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1,25-Dihydroxyvitamin D₃ Potentiates the Beneficial Effects of Allergen Immunotherapy in a Mouse Model of Allergic Asthma: Role for IL-10 and TGF-β¹

Yousef A. Taher^*,, Betty C. A. M. van Esch^*, Gerard A. Hofman^*, Paul A. J. Henricks^* and Antoon J. M. van Oosterhout^2,

^* Department of Pharmacology and Pathophysiology, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands; and Laboratory of Allergology and Pulmonary Diseases, University Medical Center Groningen, Groningen University, Groningen, The Netherlands

1,25-Dihydroxyvitamin D₃ (1,25(OH)₂D₃), a potent inhibitor of NF-B 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 TGF-β are 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 µg. Interestingly, coadministration of 10 ng of 1,25(OH)₂D₃ with 100 µg 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 TGF-β and OVA-specific IgA levels in serum. Similar effects on suboptimal immunotherapy were observed by inhibition of the NF-B pathway using the selective IB kinase 2 inhibitor PS-1145. The suppressive effects of this combined immunotherapy were partially reversed by treatment with mAb to either IL-10R or TGF-β before 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 TGF-β play a crucial role in the effector phase of this mouse model.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Research Grant 1575.1370 from Al-Fateh Medical University, Tripoli-Libya (to Y.A.T.).

² Address correspondence and reprint requests to Dr. Antoon J. M. van Oosterhout, Department of Pathology and Medical Biology, Laboratory of Allergology and Pulmonary Diseases, University Medical Center Groningen, P.O. Box: 30.001, 9700 RB, Groningen, The Netherlands. E-mail address: a.j.m.van.oosterhout{at}path.umcg.nl

³ Abbreviations used in this paper: IT, immunotherapy; 1,25(OH)₂D₃, 1,25-dihydroxyvitamin D₃; AHR, airway hyperresponsiveness; BAL, bronchoalveolar lavage; DRC, dose-response curve; Penh, enhanced pause; DC, dendritic cell; Treg, regulatory T; Tr1, T regulatory 1; mIgG, mouse IgG; rIgG, rat IgG; TLN, thoracic lymph node; IKK-2, IB kinase 2; EU, experimental unit.

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