Department of Neurology, Hospital General Universitario Gregorio Marañón, Madrid, Spain.
PLoS One. 2012;7(4):e34103. doi: 10.1371/journal.pone.0034103. Epub 2012 Apr 4.
Myeloid and plasmacytoid dendritic cells (mDCs, pDCs) are central to the initiation and the regulation of immune processes in multiple sclerosis (MS). Natalizumab (NTZ) is a humanized monoclonal antibody approved for the treatment of MS that acts by blocking expression of VLA-4 integrins on the surface of leukocytes. We determined the proportions of circulating DC subsets and analyzed expression of VLA-4 expression in 6 relapsing-remitting MS patients treated with NTZ for 1 year. VLA-4 expression levels on pDCs and mDCs decreased significantly during follow-up. In vitro coculture of peripheral blood mononuclear cells and pDCs, with different doses of NTZ in healthy controls (HC) and MS patients showed dose-dependent down-regulation of VLA-4 expression levels in both MS patients and HC, and reduced functional ability to stimulate antigen-specific T-lymphocyte responses. The biological impact of NTZ may in part be attributable to inhibition of transmigration of circulating DCs into the central nervous system, but also to functional impairment of interactions between T cells and DC.
髓系和浆细胞样树突状细胞（mDCs，pDCs）是多发性硬化症（MS）中免疫过程起始和调节的关键。那他珠单抗（NTZ）是一种人源化单克隆抗体，已被批准用于治疗多发性硬化症，其作用机制是阻断白细胞表面 VLA-4 整合素的表达。我们确定了循环 DC 亚群的比例，并分析了 6 例接受 NTZ 治疗 1 年的复发性缓解型 MS 患者的 VLA-4 表达。在随访过程中，pDCs 和 mDCs 上的 VLA-4 表达水平显著下降。在体外共培养外周血单核细胞和 pDCs，并在健康对照（HC）和 MS 患者中用不同剂量的 NTZ 进行实验，结果显示，MS 患者和 HC 中 VLA-4 表达水平均呈剂量依赖性下降，且刺激抗原特异性 T 淋巴细胞反应的功能能力降低。NTZ 的生物学影响部分可能归因于抑制循环 DC 向中枢神经系统的迁移，但也可能归因于 T 细胞和 DC 之间相互作用的功能障碍。
