Modulation of dendritic cell properties by laquinimod as a mechanism for modulating multiple sclerosis
Modulation of dendritic cell properties by laquinimod as a mechanism for modulating multiple sclerosis
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DOI：
10.1093/brain/awt023
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发表时间：
2013-04-01
期刊：
影响因子：
14.5
通讯作者：
Waisman, Ari
中科院分区：
文献类型：
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作者：
Jolivel, Valerie;Luessi, Felix;Waisman, Ari
拉喹莫德是一种口服化合物，正在研究复发缓解型多发性硬化症。为了理解拉喹莫德发挥其临床作用的机制，我们进行了评估其免疫调节特性的人和鼠研究。在实验性自身免疫性脑脊髓炎中，在SJL小鼠恢复期间开始的拉喹莫德治疗性给药如预期的那样防止了进一步复发，并大大减少了中枢神经系统中CD 4（+）和CD 8（+）T细胞的浸润。我们假设这种有益的作用是由树突状细胞介导的，因为我们和其他人发现了治疗下不同树突状细胞亚群的调节。根据对鼠系统中抗原呈递细胞的发现，我们发现用治疗浓度的拉喹莫德处理的人单核细胞来源的树突状细胞在用脂多糖成熟后诱导CD 4（+）T细胞增殖和分泌促炎细胞因子的能力降低。此外，成熟树突细胞的拉喹莫德处理导致鼠和人树突细胞的趋化因子产生减少，与单核细胞化学吸引力降低相关。在接受拉喹莫德治疗的多发性硬化患者中，我们一致发现，在脂多糖刺激下，常规CD 1c（+）树突状细胞的趋化因子和细胞因子分泌减少。与复发缓解型多发性硬化症的动物模型相似，拉喹莫德治疗后患者的树突状细胞亚群发生了改变，因为外周血单核细胞中常规CD 1c（+）和浆细胞样CD 303（+）树突状细胞的数量减少。此外，拉喹莫德治疗多发性硬化症患者和小鼠通过体内CD 86表达的上调证明了树突状细胞的成熟。我们的数据表明，NF-κ B通路的抑制是负责观察到的树突状细胞成熟和功能的变化。这些发现表明，拉喹莫德通过下调树突状细胞应答的免疫原性而在多发性硬化中表现出其疾病调节活性。我们建议在未来的治疗试验中监测多发性硬化症中的树突状细胞特性。
Laquinimod is an orally administered compound that is under investigation in relapsing-remitting multiple sclerosis. To understand the mechanism by which laquinimod exerts its clinical effects, we have performed human and murine studies assessing its immunomodulatory properties. In experimental autoimmune encephalomyelitis, the therapeutic administration of laquinimod beginning during the recovery of SJL mice, prevented further relapses as expected and strongly reduced infiltration of CD4(+) and CD8(+) T cells in the central nervous system. We hypothesized that this beneficial effect was mediated by dendritic cells, since we and others found a modulation of different dendritic cell subsets under treatment. According to the findings on antigen-presenting cells in the murine system, we found a reduced capacity of human monocyte-derived dendritic cells treated with therapeutic concentrations of laquinimod, upon maturation with lipopolysaccharide, to induce CD4(+) T cell proliferation and secretion of pro-inflammatory cytokines. Furthermore, laquinimod treatment of mature dendritic cells resulted in a decreased chemokine production by both murine and human dendritic cells, associated with a decreased monocyte chemo-attraction. In laquinimod-treated patients with multiple sclerosis we consistently found reduced chemokine and cytokine secretion by conventional CD1c(+) dendritic cells upon lipopolysaccharide stimulation. Similarly to the animal model of relapsing-remitting multiple sclerosis, dendritic cell subsets were altered in patients upon laquinimod treatment, as the number of conventional CD1c(+) and plasmacytoid CD303(+) dendritic cells were decreased within peripheral blood mononuclear cells. Moreover, laquinimod treatment in patients with multiple sclerosis and mice modified the maturation of dendritic cells demonstrated by an upregulation of CD86 expression in vivo. Our data suggest that inhibition of the NF-kappa B pathway is responsible for the changes observed in dendritic cell maturation and functions. These findings indicate that laquinimod exhibits its disease-modulating activity in multiple sclerosis by downregulating immunogenicity of dendritic cell responses. We suggest that monitoring dendritic cell properties in multiple sclerosis should be implemented in future therapeutic trials.