title: Tacrolimus and cyclosporine A inhibit allostimulatory capacity and cytokine production of human myeloid dendritic cells.
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 microg/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 alpha (P<0.04) and IL-12 (P<0.04) in response to lipopolysaccharide (1 microg/mL) or staphylococcal enterotoxin B (1 microg/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 alpha, 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.
authors.affiliation: Division of Gastroenterology, Memorial Health Center, University of Massachusetts Medical School, Worcester 01655, USA. gyongyi.szabo@umassmed.edu
authors.forename: G
authors.initials: G
authors.lastname: Szabo
authors.forename: C
authors.initials: C
authors.lastname: Gavala
authors.forename: P
authors.initials: P
authors.lastname: Mandrekar
mesh_terms: D016572:Cyclosporine / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis*; D003713:Dendritic Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007519:Isoantigens / Q000276:immunology*; D008213:Lymphocyte Activation; D009000:Monocytes / Q000187:drug effects* / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D007519:Isoantigens; D016572:Cyclosporine; D016559:Tacrolimus