Tacrolimus and cyclosporine A inhibit allostimulatory capacity and cytokine production of human myeloid dendritic cells

Myeloid dendritic cells (DCs) are pivotal in the recognition of alloantigen s and, therefore, in the induction of allograft rejection. Induction of all oreactive T cell proliferation by myeloid DCs depends on the maturation of DCs, the expression of costimulatory molecules, and the cytokine environmen t. This study investigated the effects of tacrolimus and cyclosporine A (Cs A) on DC maturation and allostimulatory capacity. Myeloid DCs were propagat ed from normal blood monocytes with interleukin (IL) 4 and GM-CSF for 7 day s in the presence or absence of tacrolimus (FK506; 10 nM) or CsA (1 mug/mL) . Exposure of DCs during maturation to tacrolimus or CsA resulted in no sig nificant change in the expression of DC phenotypic markers, including CD80, CD86, and HLA Class I and II antigens determined by now cytometry. T cell proliferation in one-way, mixed-leukocyte reaction experiments revealed a d ecreased allostimulatory capacity of DCs that matured in the presence of ta crolimus or CsA compared with untreated controls (P <0.02). Production of i nflammatory cytokines, tumor necrosis factor ce (P <0.04) and IL-12 (P <0.0 4) in response to lipopolysaccharide (1 mug/mL) or staphylococcal enterotox in B (1 mug/mL) induction was significantly reduced in DCs exposed to tacro limus or CsA during maturation. In contrast, production of the immuninhibit ory cytokine IL-10 was not decreased in tacrolimus- or CsA-treated DCs. The se results suggest that tacrolimus and CsA inhibit the allostimulatory capa city of in vitro-generated myeloid DCs without significant effects on DC ph enotypic maturation. Decreased production of IL-12 and tumor necrosis facto r ce, but not of IL-10, is likely to contribute to the impaired accessory-c ell function of tacrolimus- and CsA-treated DCs. Thus, tacrolimus and CsA c an inhibit recognition of alloantigens by decreasing the accessory-cell cap acity of monocyte-derived myeloid DCs.