IMMUNOSUPPRESSIVE EFFECTS OF 1,25-DIHYDROXYVITAMIN D-3 AND ITS ANALOGCALCIPOTRIOL ON EPIDERMAL-CELLS

1,25-Dihydroxyvitamin D-3 (1,25(OH)(2)D-3; calcitriol) is the biologic ally active form of vitamin D. This hormone is a potent immunoregulato ry agent. Calcipotriol is a synthetic analogue of 1,25(OH)(2)D-3, with similar receptor binding, and comparable effects on cell proliferatio n and differentiation, but less potent effects on calcium metabolism. As a step towards understanding the mechanisms by which vitamin D comp ounds affect T-cell activation by epidermal cells (EC), we assessed th e effects of 1,25(OH)(2)D-3 and calcipotriol on the human allogeneic m ixed epidermal cell-lymphocyte reaction. All experiments were performe d both with 1,25(OH)(2)D-3, and calcipotriol, with similar results. Bo th compounds had potent immunoinhibitory properties on this model, and enhanced the immunosuppressive effects of cyclosporin A. Using preinc ubation experiments, we found that pretreatment of EC with 1,25(OH)(2) D-3 resulted in a more pronounced inhibition than preincubation of lym phoid cells. The epidermal targets of this inhibitory effect have been further investigated, using cultures with freshly isolated Langerhans cells (LC) or LC-depleted keratinocytes, separated by an immunomagnet ic particle technique. Pretreatment of LC induced a 30% decrease of pr oliferation, compared with vehicle-treated LC. These calcitriol-pulsed LC did not decrease the proliferation induced by unmodified autologou s EC. As expected, LC-depleted keratinocytes failed to stimulate allog eneic lymphocytes. When added to autologous unmodified EC, however, ca lcitriol-pulsed keratinocytes induced an 85% decrease of proliferation , compared with vehicle-treated keratinocytes. The phenotypic expressi on of HLA-DR, -DQ, and -DP antigens on EC, assessed by immunoalkaline phosphatase staining, was not modified after a 2-h or 24-h pulse with 1,25(OH)(2)D-3 or calcipotriol. The inhibitory effect of vitamin D com pounds on EC was not modified by indomethacin, but was partially rever sed by the addition of anti-TGF-beta neutralizing antibodies. In concl usion, 1,25(OH)(2)D-3 and calcipotriol may limit the immune response i n human skin through decreased antigen presentation, mediated both by a direct effect on LC and indirectly through modulation of the product ion of cytokines by keratinocytes.