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（amyotrophiclateralsclerosis，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SOD 1的新型单克隆抗体的疫苗接种和被动免疫，并阐明小胶质细胞在突变型SOD 1相关ALS中的作用。我们发现野生型SOD 1的脱辅基形式是一种有效的疫苗相比，突变SOD 1，诱导保护性免疫与白细胞介素-4的增加和干扰素-γ和肿瘤坏死α的减少。证实了鞘内输注突变体SOD 1特异性抗体的一个克隆以减缓进展的治疗效果。我们还阐明了CD 14的小胶质细胞在细胞外SOD 1 muridium诱导的运动神经元死亡的关键作用。通过确定更关键的分子靶点或操纵单克隆抗体，可望为ALS的免疫治疗带来更大的发展。

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.