G. Szabo et al., Tacrolimus and cyclosporine A inhibit allostimulatory capacity and cytokine production of human myeloid dendritic cells, J INVES MED, 49(5), 2001, pp. 442-449
Citations number
25
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research General Topics
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.