1,25-dihydroxyvitamin D3 potentiates the in vitro inhibitory effects of cyclosporin A on T cells from rheumatoid arthritis patients.
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 effects 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.
Gepner
P
P
INSERM U, 283 Hôpital Cochin, Paris, France.
Amor
B
B
Fournier
C
C
D001172:Arthritis, Rheumatoid / Q000473:pathology*; D002117:Calcitriol / Q000008:administration & dosage / Q000494:pharmacology*; D002478:Cells, Cultured; D003524:Cyclosporins / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis; D007376:Interleukin-2 / Q000096:biosynthesis; D009000:Monocytes / Q000187:drug effects; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects*
D003524:Cyclosporins; D007375:Interleukin-1; D007376:Interleukin-2; D002117:Calcitriol