The Rheumatism Research Center, Catholic Research Institute of Medical Science, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
Division of Rheumatology, Department of Internal Medicine, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.
J Transl Med. 2021 Feb 25;19(1):86. doi: 10.1186/s12967-021-02760-2.
Autoantibody production against endogenous cellular components is pathogenic feature of systemic lupus erythematosus (SLE). Follicular helper T (T) cells aid in B cell differentiation into autoantibody-producing plasma cells (PCs). The IL-6 and IL-21 cytokine-mediated STAT3 signaling are crucial for the differentiation to T cells. Niclosamide is an anti-helminthic drug used to treat parasitic infections but also exhibits a therapeutic effect on autoimmune diseases due to its potential immune regulatory effects. In this study, we examined whether niclosamide treatment could relieve lupus-like autoimmunity by modulating the differentiation of T cells in two murine models of lupus.
10-week-old MRL/lpr mice were orally administered with 100 mg/kg of niclosamide or with 0.5% methylcellulose (MC, vehicle) daily for 7 weeks. TLR7 agonist, resiquimod was topically applied to an ear of 8-week-old C57BL/6 mice 3 times a week for 5 weeks. And they were orally administered with 100 mg/kg of niclosamide or with 0.5% MC daily for 5 weeks. Every mouse was analyzed for lupus nephritis, proteinuria, autoantibodies, immune complex, immune cell subsets at the time of the euthanization.
Niclosamide treatment greatly improved proteinuria, anti-dsDNA antibody levels, immunoglobulin subclass titers, histology of lupus nephritis, and C3 deposition in MRL/lpr and R848-induced mice. In addition, niclosamide inhibited the proportion of T cells and PCs in the spleens of these animals, and effectively suppressed differentiation of T-like cells and expression of associated genes in vitro.
Niclosamide exerted therapeutic effects on murine lupus models by suppressing T cells and plasma cells through STAT3 inhibition.
自身抗体针对内源性细胞成分的产生是红斑狼疮（SLE）的致病性特征。滤泡辅助 T（T）细胞有助于 B 细胞分化为产生自身抗体的浆细胞（PC）。IL-6 和 IL-21 细胞因子介导的 STAT3 信号对于 T 细胞的分化至关重要。尼氯硝唑是一种抗蠕虫药物，用于治疗寄生虫感染，但由于其潜在的免疫调节作用，也对自身免疫性疾病具有治疗作用。在这项研究中，我们通过在两种狼疮小鼠模型中调节 T 细胞的分化来研究尼氯硝唑治疗是否可以缓解狼疮样自身免疫。
10 周龄的 MRL/lpr 小鼠每天口服 100mg/kg 尼氯硝唑或 0.5%甲基纤维素（MC，载体），持续 7 周。TLR7 激动剂瑞喹莫德每周三次涂于耳上，持续 5 周。并且每天口服 100mg/kg 尼氯硝唑或 0.5%MC，持续 5 周。处死时分析每只小鼠的狼疮肾炎、蛋白尿、自身抗体、免疫复合物、免疫细胞亚群。
尼氯硝唑治疗显著改善了 MRL/lpr 和 R848 诱导的小鼠的蛋白尿、抗 dsDNA 抗体水平、免疫球蛋白亚类滴度、狼疮肾炎的组织学和 C3 沉积。此外，尼氯硝唑抑制了这些动物脾脏中 T 细胞和 PC 的比例，并有效抑制了体外 T 样细胞的分化和相关基因的表达。
尼氯硝唑通过抑制 STAT3 抑制 T 细胞和浆细胞，对狼疮小鼠模型发挥治疗作用。
