免疫机制在驱动多发性硬化症(MS)中起着至关重要的作用,并且在MS患者的中枢神经系统和脑脊液中观察到树突状细胞(DC)的运输和/或激活改变。干扰素β(IFNβ)已被用作MS的一线治疗近三十年,维生素D缺乏是MS公认的环境风险因素。IFNβ和维生素D均调节DC功能。这里,我们研究了用IFNβ/GM-CSF(IFN-DC)获得的DC对1,25-二羟维生素D3(1,25(OH)2D3)的反应与经典来源的IL4-DC相比,在三个供体组中:没有治疗的MS患者,接受IFNβ治疗的MS患者,健康的捐赠者除了来自MS组的IL4-DC的CCL2分泌减少外,与健康供体相比,MS供体的IFN-DC或IL4-DC的1,25(OH)2D3应答未观察到重大缺陷。然而,两种细胞模型在维生素D受体表达水平以及基础和1,25(OH)2D3诱导的细胞因子/趋化因子分泌方面存在很大差异。1,25(OH)2D3上调IL6,其可溶性受体sIL6R,和IL4-DC中的CCL5,和下调IFN-DC中的IL10。IFN-DC,但不是IL4-DC,组成型分泌高水平的IL8和基质金属蛋白酶9,均被1,25(OH)2D3下调。DC可能有助于MS的发病机制,但也为治疗干预提供了途径。1,25(OH)2D3诱导的致耐受性DC正在MS的临床试验中。我们表明,体外DC分化方案定性和定量地影响细胞因子和趋化因子的分泌,这些细胞因子和趋化因子与MS发病机理密切相关。
Immune mechanisms play an essential role in driving multiple sclerosis (MS) and altered trafficking and/or activation of dendritic cells (DC) were observed in the central nervous system and cerebrospinal fluid of MS patients. Interferon β (IFNβ) has been used as a first-line therapy in MS for almost three decades and vitamin D deficiency is a recognized environmental risk factor for MS. Both IFNβ and vitamin D modulate DC functions. Here, we studied the response to 1,25-dihydoxyvitamin D3 (1,25(OH)2D3) of DC obtained with IFNβ/GM-CSF (IFN-DC) compared to classically derived IL4-DC, in three donor groups: MS patients free of therapy, MS patients undergoing IFNβ therapy, and healthy donors. Except for a decreased CCL2 secretion by IL4-DC from the MS group, no major defects were observed in the 1,25(OH)2D3 response of either IFN-DC or IL4-DC from MS donors compared to healthy donors. However, the two cell models strongly differed for vitamin D receptor level of expression as well as for basal and 1,25(OH)2D3-induced cytokine/chemokine secretion. 1,25(OH)2D3 up-modulated IL6, its soluble receptor sIL6R, and CCL5 in IL4-DC, and down-modulated IL10 in IFN-DC. IFN-DC, but not IL4-DC, constitutively secreted high levels of IL8 and of matrix-metalloproteinase-9, both down-modulated by 1,25(OH)2D3. DC may contribute to MS pathogenesis, but also provide an avenue for therapeutic intervention. 1,25(OH)2D3-induced tolerogenic DC are in clinical
trial for MS. We show that the protocol of in vitro DC differentiation qualitatively and quantitatively affects secretion of cytokines and chemokines deeply involved in MS pathogenesis.