BACKGROUND The inflammasome adaptor apoptosis-associated speck-like protein containing a CARD (ASC) is involved in immune signaling by bridging the interactions between inflammasome sensors and caspase-1. Strong experimental evidence has shown that ASC-/- mice are protected from disease progression in animal models of multiple sclerosis (MS), suggesting that targeting inflammasome activation via ASC inhibition may be a promising therapeutic strategy in MS. Thus, the goal of our study is to test the efficacy of IC100, a novel humanized antibody targeting ASC, in preventing and/or suppressing disease in the experimental autoimmune encephalomyelitis (EAE) model of MS. METHODS We employed the EAE model of MS where disease was induced by immunization of C57BL/6 mice with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55). Mice were treated with vehicle or increasing doses of IC100 (10, 30, and 45 mg/kg) and clinical disease course was evaluated up to 35 days post EAE induction. Immune cell infiltration into the spinal cord and microglia responses were assessed. RESULTS We show that IC100 treatment reduced the severity of EAE when compared to vehicle-treated controls. At a dose of 30 mg/kg, IC100 significantly reduced the number of CD4+ and CD8+ T cells and CD11b+MHCII+ activated myeloid cells entering the spinal cord from the periphery, and reduced the number of total and activated microglia. CONCLUSIONS These data indicate that IC100 suppresses the immune-inflammatory response that drives EAE development and progression, thereby identifying ASC as a promising target for the treatment of MS as well as other neurological diseases with a neuroinflammatory component.

中文翻译：

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IC100：一种新型抗 ASC 单克隆抗体可改善多发性硬化症动物模型的功能结果。

背景含有 CARD (ASC) 的炎症小体接头凋亡相关斑点样蛋白通过桥接炎症小体传感器和 caspase-1 之间的相互作用参与免疫信号传导。强有力的实验证据表明，在多发性硬化症（MS）动物模型中，ASC-/-小鼠可以免受疾病进展，这表明通过抑制ASC来靶向炎症小体激活可能是多发性硬化症的一种有前景的治疗策略。因此，我们研究的目的是测试 IC100（一种靶向 ASC 的新型人源化抗体）在 MS 实验性自身免疫性脑脊髓炎 (EAE) 模型中预防和/或抑制疾病的功效。方法我们采用 MS 的 EAE 模型，通过用髓磷脂少突胶质细胞糖蛋白肽 35-55 (MOG35-55) 免疫 C57BL/6 小鼠来诱导疾病。小鼠接受媒介物或增加剂量的 IC100（10、30 和 45 mg/kg）治疗，并在 EAE 诱导后 35 天评估临床病程。评估免疫细胞浸润脊髓和小胶质细胞反应。结果我们表明，与媒介物治疗对照相比，IC100 治疗降低了 EAE 的严重程度。在30 mg/kg的剂量下，IC100显着减少了从外周进入脊髓的CD4+和CD8+ T细胞以及CD11b+MHCII+激活的骨髓细胞的数量，并减少了总的和激活的小胶质细胞的数量。结论 这些数据表明 IC100 抑制了驱动 EAE 发生和进展的免疫炎症反应，从而确定 ASC 是治疗 MS 以及具有神经炎症成分的其他神经系统疾病的有希望的靶点。