1,25‐Dihydroxyvitamin D3 POtentiates the in vitro inhibitory effects of cyclosporin A on T cells from rheumatoid arthritis patients

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Abstract
Treatment of rheumatoid arthritis (RA) with cyclosporin A (CsA) has been successful, but the adverse effects of the drug have limited its use. We investigated the capacity of another immunosuppressive agent, 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3], to augment the effect of CsA on in vitro T cell functions. Exposure of CD4+ cells from RA patients or from normal subjects to either molecule alone resulted in a dose‐dependent inhibition of phytohemagglutinin stimulation and interleukin‐2 (IL‐2) production that was more pronounced in cells from RA patients than in cells from normal subjects. Moreover, the action of CsA and 1, 25(OH)2D3 on RA patient T cell functions in vitro was synergistic. Thus, in the presence of the vitamin D3 metabolite, only one‐hundredth the concentration of CsA was required to produce the same effect on IL‐2 production as that produced by CsA alone. IL‐2 receptor expression was also reduced by the addition of both drugs. In contrast, IL‐1 production by RA monocytes was not affected by CsA and 1,25(OH)2D3, either together or alone, and addition of IL‐1 did not restore the ability of CD4+ cells from RA patients to secrete IL‐2. Exogenous IL‐2 reversed a large part of the inhibitory effect induced by both CsA and 1, 25(OH)2D3, indicating that the immunosuppressive properties of these agents are mediated by the inhibition of IL‐2 secretion. This synergy between 2 molecules that are biochemically very different suggests the existence of one or several sites of interaction that take place during the early stages of T cell activation.