Szabo G, Gavala C, Mandrekar P
Division of Gastroenterology, Memorial Health Center, University of Massachusetts Medical School, Worcester 01655, USA.
J Investig Med. 2001 Sep;49(5):442-9. doi: 10.2310/6650.2001.33789.
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.
髓样树突状细胞（DCs）在同种异体抗原的识别中起关键作用，因此在同种异体移植排斥反应的诱导中也起关键作用。髓样DCs诱导同种异体反应性T细胞增殖取决于DCs的成熟、共刺激分子的表达以及细胞因子环境。本研究调查了他克莫司和环孢素A（CsA）对DC成熟和同种异体刺激能力的影响。在有或没有他克莫司（FK506；10 nM）或CsA（1 μg/mL）存在的情况下，用白细胞介素（IL）-4和粒细胞巨噬细胞集落刺激因子（GM-CSF）从正常血液单核细胞中培养髓样DCs 7天。DCs在成熟过程中暴露于他克莫司或CsA，通过流式细胞术检测发现DC表型标志物（包括CD80、CD86以及HLA I类和II类抗原）的表达没有显著变化。单向混合淋巴细胞反应实验中的T细胞增殖显示，与未处理的对照相比，在他克莫司或CsA存在下成熟的DCs的同种异体刺激能力降低（P<0.02）。在成熟过程中暴露于他克莫司或CsA的DCs，在受到脂多糖（1 μg/mL）或葡萄球菌肠毒素B（1 μg/mL）诱导时，炎性细胞因子肿瘤坏死因子α（P<0.04）和IL-12（P<0.04）的产生显著减少。相比之下，在经他克莫司或CsA处理的DCs中，免疫抑制细胞因子IL-10的产生没有减少。这些结果表明，他克莫司和CsA抑制体外生成的髓样DCs的同种异体刺激能力，而对DC表型成熟没有显著影响。IL-12和肿瘤坏死因子α的产生减少，但IL-10没有减少，这可能导致经他克莫司和CsA处理的DCs的辅助细胞功能受损。因此，他克莫司和CsA可通过降低单核细胞来源的髓样DCs的辅助细胞能力来抑制同种异体抗原的识别。
