Immunization with a Myelin-Derived Antigen Activates the Brain's Choroid Plexus for Recruitment of Immunoregulatory Cells to the CNS and Attenuates Disease Progression in a Mouse Model of ALS
Immunization with a Myelin-Derived Antigen Activates the Brain's Choroid Plexus for Recruitment of Immunoregulatory Cells to the CNS and Attenuates Disease Progression in a Mouse Model of ALS
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DOI：
10.1523/jneurosci.3644-14.2015
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发表时间：
2015-04-22
影响因子：
5.3
通讯作者：
Schwartz, Michal
中科院分区：
文献类型：
--
作者：
Kunis, Gilad;Baruch, Kuti;Schwartz, Michal
肌萎缩侧索硬化症（ALS）是一种毁灭性的致命运动神经元疾病，目前还没有治愈或有效的治疗方法。在这种疾病中，局部神经炎症沿着病程发展并促进其快速进展。在几种CNS病理模型中，循环免疫细胞显示出在神经炎症反应的解决中不可或缺的作用。这些细胞向CNS的募集涉及通过需要IFN-γ信号传导的机制激活脑的脉络丛（CP）用于白细胞运输。在这里，我们发现在ALS的突变型SOD 1（G93 Lambda）（mSOD 1）小鼠模型中，由于IFN-γ水平的局部降低，CP不支持疾病进展期间的白细胞运输。用髓磷脂衍生肽对mSOD 1小鼠进行治疗性免疫导致CP激活，随后是免疫调节细胞的积累，包括IL-10产生单核细胞衍生的巨噬细胞和Foxp 3（+）调节性T细胞，以及患病脊髓实质中神经营养因子IGF-1和GDNF的升高。免疫导致疾病进展的减弱和mSOD 1小鼠预期寿命的增加。总的来说，我们的研究结果表明，招募免疫调节细胞的患病脊髓ALS，需要对抗的病理，可以提高瞬时增强外周免疫髓鞘抗原。
Amyotrophic lateral sclerosis (ALS) is a devastating fatal motor neuron disease, for which there is currently no cure or effective treatment. In this disease, local neuroinflammation develops along the disease course and contributes to its rapid progression. In several models of CNS pathologies, circulating immune cells were shown to display an indispensable role in the resolution of the neuroinflammatory response. The recruitment of such cells to the CNS involves activation of the choroid plexus (CP) of the brain for leukocyte trafficking, through a mechanism that requires IFN-gamma signaling. Here, we found that in the mutant SOD1(G93 Lambda) (mSOD1) mouse model of ALS, the CP does not support leukocyte trafficking during disease progression, due to a local reduction in IFN-gamma levels. Therapeutic immunization of mSOD1 mice with a myelin-derived peptide led to CP activation, and was followed by the accumulation of immunoregulatory cells, including IL-10-producing monocyte-derived macrophages and Foxp3 (+) regulatory T cells, and elevation of the neurotrophic factors IGF-1 and GDNF in the diseased spinal cord parenchyma. The immunization resulted in the attenuation of disease progression and an increased life expectancy of the mSOD1 mice. Collectively, our results demonstrate that recruitment of immunoregulatory cells to the diseased spinal cord in ALS, needed for fighting off the pathology, can be enhanced by transiently boosting peripheral immunity to myelin antigens.