title: Diltiazem induces regulatory T cells in vitro by modulating human dendritic cell maturation.
abstract: Diltiazem is a calcium channel antagonist that has been commonly associated with currently used immunosuppressants to prevent acute graft rejection in humans. In this study, we examined the possibility that diltiazem may affect human dendritic cell (DC) functions in response to lipopolysaccharide (LPS) stimulation and may induce the generation of DC with the capacity to generate CD4(+) regulatory T cells (Tregs). Blood monocytes were cultured in the presence of diltiazem at the beginning of their differentiation process into DC. Monocyte-derived DCs were stimulated with LPS, and DCs differentiated in the presence of diltiazem showed a decreased interleukin (IL)-12 production and an enhanced IL-10 production. When cultured with CD4(+) CD45RA(+) they were able to enhance the CD4(+) Foxp3(+) T-cell population and to induce slowly proliferating T cells, which showed a significant increase of transforming growth factor (TGF)-β production. These T cells suppress proliferation of activated autologous T cells, and we show that this effect is attributable to soluble factors, primarily to TGF-β. Blockade of TGF-β by specific monoclonal antibodies reversed this inhibitory effect. Herein, we provide new evidence that diltiazem-conditioned monocyte-derived DC induce T cells which acquire a regulatory phenotype and activity similar to those described for Tregs.
authors.affiliation: Section of Immune-mediated Diseases, Department of Infectious, Parasitic and Immune-mediated Diseases, Istituto Superiore di Sanità, Rome, Italy.
authors.forename: Orsola
authors.initials: O
authors.lastname: Pugliese
authors.forename: Antonella
authors.initials: A
authors.lastname: D'Ambrosio
authors.forename: Doriana
authors.initials: D
authors.lastname: Campanile
authors.forename: Francesca
authors.initials: F
authors.lastname: Quintieri
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology* / Q000187:drug effects; D004110:Diltiazem / Q000494:pharmacology*; D006801:Humans; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects*
chemical_list: D004110:Diltiazem