The rationale for such a strategy is further strengthened by evidence that existing therapies for allergic diseases, such as allergen immunotherapy and glucocorticoids, are associated with the induction of Treg cells in patients [2]. Nevertheless, considerable scope for improving the safety and efficacy of these treatments exists. Recent studies have focused on the capacity of vitamin D to modulate Treg-cell subsets. For example, culturing dendritic cells (DCs) with PD98059 research buy the active form of vitamin D, 1α,25-dihydroxyvitamin D3 (1α25VitD3) leads to impaired DC maturation, development of

tolerogenic properties [3], and the capacity to induce CD4+Foxp3+ cells with suppressive activity [4], or IL-10 expressing Treg cells [5]. In animal models of human disease, administration of 1α25VitD3 successfully treats transplant rejection [6] and a range of autoimmune conditions, including antiretinal autoimmunity [7], acute colitis [8], diabetes [6], arthritis [9], and EAE [10], as well as allergic airway disease [11]. PI3K Inhibitor Library These studies demonstrate a correlation between therapeutic efficacy and increased frequency or quantities of CD4+CD25+ T cells, IL-10, TGF-β, and CTLA-4. Our earlier studies have highlighted the capacity of 1α25VitD3 to promote human CD4+ IL-10 secreting

Treg cells (IL-10-Treg) in culture both alone [12] and in concert with glucocorticoids such as dexamethasone [13, 14]. Furthermore, treatment of severe steroid refractory asthma patients with 1α25VitD3 in vivo directly increased IL-10 gene expression

in CD3+CD4+ T cells [12], and restored the impaired steroid-induced IL-10 response in CD4+ cells in vitro [14, 15]. The present study was designed to further investigate the mechanisms underlying the therapeutic potential of 1α25VitD3 in the context of asthmatic disease, and to determine effects on the induction of both IL-10+ and Foxp3+ T cells. Specifically, we have examined the effects of 1α25VitD3 on total, unfractionated CD4+ T-cell populations, representative of those likely to be encountered in vivo. The data demonstrate that 1α25VitD3 increases the frequency not only of IL-10-Treg cells, but also of Foxp3+ Treg cells, that these cells express increased levels of the inhibitory receptors CTLA-4 and PD-1, and exhibit inhibitory PTK6 function. The data further suggest that 1α25VitD3 functions to maintain Foxp3 expression in the existing Foxp3+ Treg-cell pool. We have previously described the induction of IL-10 secreting cells following culture of human CD4+ T cells with 1α25VitD3 in vitro and directly ex vivo following administration of calcitriol to asthma patients [12, 14]. An unusual dose response was observed in vitro with 1α25VitD3 at the very highest concentration tested (10−6 M 1α25VitD3) resulting in considerably lower IL-10 secretion than the optimal concentrations of 10−7 M and 10−8 M 1α25VitD3 [12].