Vitamin D for the Treatment of Severe Asthma

Glucocorticoids are the first-line antiinflammatory treatment for asthma. Their multiple inhibitory properties, including the inhibition of Th2 cytokine synthesis, are likely to contribute to clinical efficacy. Glucocorticoids also enhance IL-10 production in vitro by human CD4+ and CD8+ T cells, and glucocorticoid treatment induces the synthesis of IL-10 by airway cells in asthmatic patients. IL-10 is a potent antiinflammatory and immunosuppressive leading to profound inhibition of Th1 cell-mediated immunity. A proportion of asthmatic patients fails to benefit from oral glucocorticoid therapy and are thus denoted as having glucocorticoid-resistant (SR, derived from "steroid resistant") or insensitive asthma. It has been demonstrated that CD4+ T cells from SR asthma patients fail to induce IL-10 synthesis following in vitro stimulation in the presence of dexamethasone as compared with their glucocorticoid-sensitive counterparts (SS, derived from "steroid sensitive"), suggesting a link between induction of IL-10 synthesis and clinical efficacy of glucocorticoids. One potential source of IL-10 is Tregs, which control the function of effector T cells. Glucocorticoids enhance the production of IL-10 by polyclonally stimulated T cells and these cells inhibit IFN- production by human CD4+ T cells in an IL-10-dependent manner. In both mouse and human a combination of dexamethasone and calcitriol, the active form of vitamin D3, induced high numbers of IL-10-producing T cells that made negligible amounts of Th1 and Th2 cytokines. Xystrakis et al. (57) showed that IL-10-secreting Tregs inhibit cytokine production by previously activated allergen-specific Th2 cells and that pretreating T cells with IL-10 or adding vitamin D3 to the cell cultures can reverse the defect and enhance IL-10 production by Tregs from asthmatic patients who were resistant to glucocorticoid therapy. These manipulations increase IL-10 production to levels comparable to those observed in patients who do respond well to therapy. IL-10 increases glucocorticoid receptor expression, and the authors proposed that this is the mechanism by which IL-10 overcomes the glucocorticoid-resistant patient defect in IL-10 synthesis. This strongly suggests that vitamin D3 could potentially increase the therapeutic response to glucocorticoids in SR patients. We want to test the hypothesis, that vitamin D3 improves pulmonary function and quality of life in patients with asthma relatively resistant to glucocorticoids.