CD200R1 agonist attenuates mechanisms of chronic disease in a murine model of multiple sclerosis.
CD200R1 agonist attenuates mechanisms of chronic disease in a murine model of multiple sclerosis.
复制标题
DOI：
10.1523/jneurosci.4272-09.2010
复制
发表时间：
2010-02-10
期刊：
影响因子：
--
通讯作者：
Chitnis T
中科院分区：
文献类型：
--
作者：
Liu Y;Bando Y;Vargas-Lowy D;Elyaman W;Khoury SJ;Huang T;Reif K;Chitnis T
为了评估在多发性硬化模型的进展阶段期间施用的CD 200 R1激动剂的作用和机制，我们在患有实验性自身免疫性脑脊髓炎（EAE）的小鼠的疾病慢性期（第10-30天）期间施用CD 200 R1激动剂（CD 200 Fc）或对照IgG 2a，所述实验性自身免疫性脑脊髓炎（EAE）使用MOG 35 -55肽诱导。我们发现，在EAE的慢性阶段给予CD 200 R1激动剂（CD 200 Fc）通过调节几种关键的疾病机制，降低了疾病的严重程度、脱髓鞘和轴突损伤。CD 200 Fc处理抑制巨噬细胞和小胶质细胞在CNS内的积聚，部分通过下调巨噬细胞迁移所必需的粘附分子VLA-4和LFA-1。此外，在CD 200 Fc处理动物的脾脏和CNS中，活化标志物MHC-II和CD 80的表达以及CD 11b+细胞产生的促炎细胞因子IL-6、TNF-α和一氧化氮均降低。在CD 200 Fc处理的小鼠中，脾脏和CNS中的APC功能被抑制，但T细胞活化或表型没有显著改变。CD 200 Fc增加了CD 11b+细胞的凋亡，但不增加星形胶质细胞的凋亡。相反，加入CD 200 Fc治疗在体外和体内保护少突胶质细胞免于凋亡。我们的研究结果表明，CD 200 R1激动剂调节EAE模型中慢性疾病的髓系和非髓系相关机制，并可能有效治疗进行性MS和其他神经退行性疾病。
To assess the effects and mechanisms of a CD200R1 agonist administered during the progressive stage of a multiple sclerosis model, we administered CD200R1 agonist (CD200Fc) or control IgG2a during the chronic phase of disease (days 10–30) in mice with experimental autoimmune encephalomyelitis (EAE), induced using MOG35–55 peptide. We found that administration of a CD200R1 agonist (CD200Fc) during the chronic stages of EAE reduced disease severity, demyelination and axonal damage, through the modulation of several key disease mechanisms. CD200Fc treatment suppressed macrophage and microglial accumulation within the CNS, in part through downregulation of adhesion molecules VLA-4 and LFA-1, which are necessary for macrophage migration. Additionally, expression of activation markers MHC-II and CD80 and production of pro-inflammatory cytokines IL-6, TNF-α and nitric oxide by CD11b+ cells were decreased in both the spleen and CNS in CD200Fc treated animals. APC function in the spleen and CNS was suppressed in CD200Fc treated mice, but there were no significant alterations on T cell activation or phenotype. CD200Fc increased apoptosis of CD11b+ cells, but not astrocytes. In contrast, addition of CD200Fc treatment protected oligodendrocytes from apoptosis in vitro and in vivo. Our results demonstrate that CD200R1 agonists modulate both myeloid and non-myeloid related mechanisms of chronic disease in the EAE model, and may be effective in the treatment of progressive MS and other neurodegenerative diseases.