Department of Radiation Oncology, Far Eastern Memorial Hospital, Taipei, Taiwan.
Transplantation. 2011 Oct 27;92(8):848-57. doi: 10.1097/TP.0b013e31822d8708.
To examine the effects of norcantharidin (NCTD) on development of human myeloid dendritic cells (DCs) in vitro and in skin allograft transplantation in vivo.
Human CD14(+) monocytes were isolated and triggered differentiation and maturation toward myeloid DCs with and without NCTD. The cell morphology, viability, cell death, expression of surface markers and co-stimulatory molecules, allostimulatory activity, and cytokine production were examined for characterization of DCs. The rejection of mice skin allograft model was used to translate the in vitro effect of cantharidin (CTD) and NCTD on DCs.
DCs developed in the presence of NCTD showed decreased viability, cell death with necrosis, and lower expression of CD1a and CD83. DCs triggered in the presence of NCTD possessed a greater allostimulatory activity in naive CD4(+)CD45RA(+) T cells. NCTD modulated DCs through calcineurin phosphatase but not through mammalian target of rapamycin or downstream molecule p70S6 kinase. In vivo, NCTD caused accumulation and co-localization of antigen-presenting cells and regulatory T cells in the interfollicular area of the recipients' spleens. CTD and NCTD prolonged skin allograft survival along with less severe histopathological inflammatory reactions. CTD, but not NCTD, treatment caused elevation of serum alanine aminotransferase and evident mortality of the recipients.
NCTD modulated the differentiation and maturation of human myeloid DCs and caused deviation of standard DC differentiation toward a tolerogenic phenotype through calcineurin phosphatase inhibition. In vivo, both drugs effectively prolonged skin allograft survival. NCTD was less toxic than CTD, and thus, has potential for development as an immunosuppressant for transplant rejection.
研究去甲斑蝥素（NCTD）对人源髓系树突状细胞（DC）体外发育和体内皮肤移植排斥反应的影响。
从人外周血单个核细胞中分离 CD14+单核细胞，用 NCTD 处理和未处理的细胞分别向髓系 DC 分化和成熟。检测细胞形态、活力、细胞死亡、表面标记物和共刺激分子表达、混合淋巴细胞反应和细胞因子分泌，以鉴定 DC。通过建立小鼠皮肤移植排斥模型，将斑蝥素（CTD）和 NCTD 对 DC 的体外作用转化为体内作用。
NCTD 存在的情况下发育的 DC 活力降低，坏死性细胞死亡增加，CD1a 和 CD83 表达降低。在 NCTD 存在下诱导的 DC 在幼稚 CD4+CD45RA+T 细胞中具有更强的共刺激活性。NCTD 通过钙调神经磷酸酶而不是哺乳动物雷帕霉素靶蛋白或下游分子 p70S6 激酶调节 DC。在体内，NCTD 导致抗原呈递细胞和调节性 T 细胞在受者脾脏的滤泡间区积聚和共定位。CTD 和 NCTD 延长皮肤移植物的存活时间，同时减轻组织病理学炎症反应的严重程度。CTD 而不是 NCTD 治疗导致受者血清丙氨酸氨基转移酶升高和明显的死亡率。
NCTD 调节人源髓系 DC 的分化和成熟，并通过抑制钙调神经磷酸酶导致标准 DC 分化向耐受表型的偏离。在体内，两种药物均有效延长皮肤移植物的存活时间。NCTD 比 CTD 的毒性更小，因此有潜力开发为用于移植排斥反应的免疫抑制剂。
