Abstract
Myeloid dendritic cells (DCs) are pivotal in the recognition of alloantigens and, therefore, in the induction of allograft rejection. Induction of alloreactive T cell proliferation by myeloid DCs depends on the maturation of DCs, the expression of costimulatory molecules, and the cytokine environment. This study investigated the effects of tacrolimus and cyclosporine A (CsA) on DC maturation and allostimulatory capacity. Myeloid DCs were propagated from normal blood monocytes with interleukin (IL) 4 and GM-CSF for 7 days in the presence or absence of tacrolimus (FK506; 10 nM) or CsA (1 μg/mL). Exposure of DCs during maturation to tacrolimus or CsA resulted in no significant change in the expression of DC phenotypic markers, including CD80, CD86, and HLA Class I and II antigens determined by flow cytometry. T cell proliferation in one-way, mixed-leukocyte reaction experiments revealed a decreased allostimulatory capacity of DCs that matured in the presence of tacrolimus or CsA compared with untreated controls (P<0.02). Production of inflammatory cytokines, tumor necrosis factor α (P<0.04) and IL-12 (P<0.04) in response to lipopolysaccharide (1 μg/mL) or staphylococcal enterotoxin B (1 μg/mL) induction was significantly reduced in DCs exposed to tacrolimus or CsA during maturation. In contrast, production of the immuninhibitory cytokine IL-10 was not decreased in tacrolimus- or CsA-treated DCs. These results suggest that tacrolimus and CsA inhibit the allostimulatory capacity of in vitro-generated myeloid DCs without significant effects on DC phenotypic maturation. Decreased production of IL-12 and tumor necrosis factor a, but not of IL-10, is likely to contribute to the impaired accessory-cell function of tacrolimus- and CsA-treated DCs. Thus, tacrolimus and CsA can inhibit recognition of alloantigens by decreasing the accessory-cell capacity of monocyte-derived myeloid DCs.
| Original language | English |
|---|---|
| Pages (from-to) | 442-449 |
| Number of pages | 8 |
| Journal | Journal of Investigative Medicine |
| Volume | 49 |
| Issue number | 5 |
| Publication status | Published - 2001 |
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Keywords
- Interleukin 10
- Interleukin 12
- Mixedlymphocyte reaction
- Monocyte
- Tumor necrosis factor α
ASJC Scopus subject areas
- Medicine(all)
- Biochemistry, Genetics and Molecular Biology(all)
Cite this
Tacrolimus and cyclosporine A inhibit allostimulatory capacity and cytokine production of human myeloid dendritic cells. / Szabó, G.; Gavala, C.; Mandrekar, P.
In: Journal of Investigative Medicine, Vol. 49, No. 5, 2001, p. 442-449.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Tacrolimus and cyclosporine A inhibit allostimulatory capacity and cytokine production of human myeloid dendritic cells
AU - Szabó, G.
AU - Gavala, C.
AU - Mandrekar, P.
PY - 2001
Y1 - 2001
N2 - Myeloid dendritic cells (DCs) are pivotal in the recognition of alloantigens and, therefore, in the induction of allograft rejection. Induction of alloreactive T cell proliferation by myeloid DCs depends on the maturation of DCs, the expression of costimulatory molecules, and the cytokine environment. This study investigated the effects of tacrolimus and cyclosporine A (CsA) on DC maturation and allostimulatory capacity. Myeloid DCs were propagated from normal blood monocytes with interleukin (IL) 4 and GM-CSF for 7 days in the presence or absence of tacrolimus (FK506; 10 nM) or CsA (1 μg/mL). Exposure of DCs during maturation to tacrolimus or CsA resulted in no significant change in the expression of DC phenotypic markers, including CD80, CD86, and HLA Class I and II antigens determined by flow cytometry. T cell proliferation in one-way, mixed-leukocyte reaction experiments revealed a decreased allostimulatory capacity of DCs that matured in the presence of tacrolimus or CsA compared with untreated controls (P<0.02). Production of inflammatory cytokines, tumor necrosis factor α (P<0.04) and IL-12 (P<0.04) in response to lipopolysaccharide (1 μg/mL) or staphylococcal enterotoxin B (1 μg/mL) induction was significantly reduced in DCs exposed to tacrolimus or CsA during maturation. In contrast, production of the immuninhibitory cytokine IL-10 was not decreased in tacrolimus- or CsA-treated DCs. These results suggest that tacrolimus and CsA inhibit the allostimulatory capacity of in vitro-generated myeloid DCs without significant effects on DC phenotypic maturation. Decreased production of IL-12 and tumor necrosis factor a, but not of IL-10, is likely to contribute to the impaired accessory-cell function of tacrolimus- and CsA-treated DCs. Thus, tacrolimus and CsA can inhibit recognition of alloantigens by decreasing the accessory-cell capacity of monocyte-derived myeloid DCs.
AB - Myeloid dendritic cells (DCs) are pivotal in the recognition of alloantigens and, therefore, in the induction of allograft rejection. Induction of alloreactive T cell proliferation by myeloid DCs depends on the maturation of DCs, the expression of costimulatory molecules, and the cytokine environment. This study investigated the effects of tacrolimus and cyclosporine A (CsA) on DC maturation and allostimulatory capacity. Myeloid DCs were propagated from normal blood monocytes with interleukin (IL) 4 and GM-CSF for 7 days in the presence or absence of tacrolimus (FK506; 10 nM) or CsA (1 μg/mL). Exposure of DCs during maturation to tacrolimus or CsA resulted in no significant change in the expression of DC phenotypic markers, including CD80, CD86, and HLA Class I and II antigens determined by flow cytometry. T cell proliferation in one-way, mixed-leukocyte reaction experiments revealed a decreased allostimulatory capacity of DCs that matured in the presence of tacrolimus or CsA compared with untreated controls (P<0.02). Production of inflammatory cytokines, tumor necrosis factor α (P<0.04) and IL-12 (P<0.04) in response to lipopolysaccharide (1 μg/mL) or staphylococcal enterotoxin B (1 μg/mL) induction was significantly reduced in DCs exposed to tacrolimus or CsA during maturation. In contrast, production of the immuninhibitory cytokine IL-10 was not decreased in tacrolimus- or CsA-treated DCs. These results suggest that tacrolimus and CsA inhibit the allostimulatory capacity of in vitro-generated myeloid DCs without significant effects on DC phenotypic maturation. Decreased production of IL-12 and tumor necrosis factor a, but not of IL-10, is likely to contribute to the impaired accessory-cell function of tacrolimus- and CsA-treated DCs. Thus, tacrolimus and CsA can inhibit recognition of alloantigens by decreasing the accessory-cell capacity of monocyte-derived myeloid DCs.
KW - Interleukin 10
KW - Interleukin 12
KW - Mixedlymphocyte reaction
KW - Monocyte
KW - Tumor necrosis factor α
UR - http://www.scopus.com/inward/record.url?scp=0034883212&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0034883212&partnerID=8YFLogxK
M3 - Article
C2 - 11523700
AN - SCOPUS:0034883212
VL - 49
SP - 442
EP - 449
JO - Journal of Investigative Medicine
JF - Journal of Investigative Medicine
SN - 1081-5589
IS - 5
ER -