Center for Innovation in Immunoregulation Technology and Therapeutics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
Drug Discovery Research, Astellas Pharma Inc., Tsukuba, Ibaraki, Japan.
Mod Rheumatol. 2024 Feb 26;34(2):359-368. doi: 10.1093/mr/road024.
Several animal disease models have been used to understand the mechanisms of systemic lupus erythematosus (SLE); however, the translation of findings from animals to humans has not been sufficiently examined in drug development. To confirm the validity of New Zealand black x New Zealand white (NZB/W) F1 mice as an SLE model, we extensively characterized SLE patients and NZB/W F1 mice by omics analysis.
Peripheral blood from patients and mice and spleen and lymph node tissue from mice were analysed using cell subset analysis, cytokine panel assays, and transcriptome analysis.
CD4+ effector memory T cells, plasmablasts, and plasma cells were increased in both SLE patients and NZB/W F1 mice. Levels of tumor necrosis factor-α, interferon gamma induced protein-10, and B cell activating factor in plasma were significantly higher in SLE patients and NZB/W F1 mice than in their corresponding controls. Transcriptome analysis revealed an upregulation of genes involved in the interferon signalling pathway and T-cell exhaustion signalling pathway in both SLE patients and the mouse model. In contrast, death receptor signalling genes showed changes in the opposite direction between patients and mice.
NZB/W F1 mice are a generally suitable model of SLE for analysing the pathophysiology and treatment response of T/B cells and monocytes/macrophages and their secreted cytokines.
已经有几种动物疾病模型被用于理解系统性红斑狼疮（SLE）的发病机制；然而，在药物开发中，从动物到人类的研究结果的转化尚未得到充分的研究。为了确认新西兰黑×新西兰白（NZB/W）F1 小鼠作为 SLE 模型的有效性，我们通过组学分析对 SLE 患者和 NZB/W F1 小鼠进行了广泛的特征描述。
通过细胞亚群分析、细胞因子谱分析和转录组分析，对患者和小鼠的外周血以及小鼠的脾脏和淋巴结组织进行了分析。
在 SLE 患者和 NZB/W F1 小鼠中，CD4+效应记忆 T 细胞、浆母细胞和浆细胞均增加。SLE 患者和 NZB/W F1 小鼠的血浆中肿瘤坏死因子-α、干扰素γ诱导蛋白-10 和 B 细胞激活因子的水平明显高于其相应的对照。转录组分析显示，SLE 患者和小鼠模型中，干扰素信号通路和 T 细胞耗竭信号通路相关基因上调。相比之下，死亡受体信号通路基因在患者和小鼠中呈现相反的变化趋势。
NZB/W F1 小鼠是一种普遍适用的 SLE 模型，可用于分析 T/B 细胞、单核细胞/巨噬细胞及其分泌的细胞因子的病理生理学和治疗反应。
