Development of an immunotherapy against ALS model mice and analysis of the role of microglia in the pathogenesis of ALS

肌萎缩侧索硬化症(ALS)是一种病因不明的致死性神经退行性疾病。本研究的目的是利用ALS模型小鼠改进针对突变型SOD1的新型单抗的免疫接种和被动免疫，并阐明小胶质细胞在突变型SOD1连锁ALS中的作用。我们发现，与突变型SOD1相比，突变型WT SOD1是一种有效的疫苗，其诱导的保护性免疫是通过增加IL-4、降低干扰素-γ和肿瘤坏死α来实现的。鞘内注射一种突变型SOD1特异性抗体以延缓病情进展的治疗效果得到证实。我们还阐明了小胶质细胞的CD14在细胞外SOD1突变诱导的运动神经元死亡中的关键作用。通过定义更关键的分子靶点或操纵单抗，可以预期ALS免疫治疗的进一步发展。

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with unknown etiology. The aim of this research project was to improve the vaccination and a passive immunization with a novel monoclonal antibody against mutant SOD1 using ALS model mice, and to clarify the roles of microglia in mutant SOD1-linked ALS. We found apo-form of WT SOD1 is an effective vaccine compared with mutant SOD1, which induces a protective immunity with the increase in interleukin-4 and the decrease in interferon-gamma and tumor necrosis alpha. The therapeutic effect of intrathecal infusion of one clone of the mutant SOD1-specific antibodies to slow the progression was confirmed. We also clarified the crucial role of CD14 of the microglia in extracellular SOD1 mutant-induced motor neuron death. Further development of immunotherapy for ALS can be anticipated by defining more crucial molecular target or manipulating monoclonal antibody.