Targeting the vitamin D receptor inhibits the B cell-dependent allergic immune response

P>Background: 1 alpha,25-dihydroxyvitamin D-3 (calcitriol), the biologically active form of vitamin D, is an immunomodulatory hormone, e.g. it inhibits IgE synthesis in B cells. As its clinical application is limited by hypercalcemia, synthetic vitamin D receptor (VDR) agonists that mediate immunomodulatory activities without adverse hypercalcemic effects are of great interest. This study aimed to investigate the impact of a low-calcemic VDR agonist on the IgE immune response in vitro and in vivo. Methods: Human peripheral B cells were cultured under IgE inducing conditions in the presence of VDR ligands. B cells were analyzed by quantitative RT-PCR, enzyme-linked immunosorbent assays, enzyme-linked immunospot technique, and flow cytometry. BALB/c mice were sensitized with ovalbumin (OVA)/alum followed by the therapeutic VDR agonist treatment and analyzed regarding the humoral immunoglobulin profile. Results: The natural VDR ligand calcitriol, but also a low-calcemic VDR agonist, profoundly suppressed IgE production by human peripheral B cells by 63.9 +/- 5.9%. The potential mechanisms involved are the reduction of the transcript for activation-induced deaminase (AID) and the reduction of IgE immunoglobulin-secreting cells by 68.1 +/- 12.7%. By using an in vivo approach, we finally demonstrate that the humoral IgE response in a type I allergy mouse model was impaired by the VDR agonist. Conclusion: Our results show that targeting the VDR modulates the humoral immune response including IgE. Whether it might be useful for clinical applications has to be determined in appropriate clinical trials.