不只在今天被看见——SLE动物模型加速“可治愈未来”到来


每年的5月10日是“世界狼疮日”,主题是——Make Lupus Visible · 让狼疮显现。这一天,是为了让全球更多人关注这种被称为“千面疾病”的复杂病症——系统性红斑狼疮。

系统性红斑狼疮

系统性红斑狼疮是一种复杂且异质性很高的自身免疫病,多发于育龄期女性,其根本原因是免疫系统的紊乱。在遗传易感性与环境因素(如紫外线、病毒感染)的交互作用下,机体免疫耐受崩溃,导致自身反应性T细胞和B细胞异常活化、致病性自身抗体大量产生及免疫复合物在全身多脏器沉积。系统性红斑狼疮被称为“伟大的模仿者”,该病可模拟多种疾病,临床表现多样且多变,可引起狼疮性肾炎、关节炎、皮肤蝶形红斑、中枢神经系统损害乃至溶血性贫血。

图. 免疫激活物质的过度生产导致SLE发病的作用机制[1]

SLE与相关动物模型研究

由于SLE的病因复杂,动物模型是理解其发病机制和验证新疗法的关键工具。南模生物长期致力于自身免疫性疾病相关研究,利用降植烷诱导模型、人源化模型等方式开发了多种系统性红斑狼疮小鼠模型,为相关药物的药效评估和安全性评价提供了强有力的工具。


诱导模型


Pristane腹腔注射诱导的小鼠模型是研究系统性红斑狼疮相关免疫复合物性肾炎的经典动物模型。降植烷作为一种无法代谢的烷烃,会长期停留在腹腔中,被巨噬细胞等免疫细胞吞噬,趋化淋巴细胞聚集,持续激活I型干扰素信号通路,促进自身抗体产生,从而导致免疫复合物沉积导致全身损伤。

南模生物可提供Pristane诱导的BALB/c、C57BL/6系统性红斑狼疮模型,部分数据如下:

验证数据:


Fig.1 Body weight of SLE model in BALB/c and C57BL/6 mice.

Fig.2 SLE model in BALB/c and C57BL/6 mice. (A) Serum anti-dsDNA IgG Ab at 6 weeks post administration, (B) Serum anti-dsDNA IgG Ab at 12 weeks post administration.

Fig.3 HE staining results and analysis of the SLE model. (*P<0.05,***P<0.001)

咪喹莫特(Imiquimod, IMQ)可通过外源性TLR7信号通路的持续异常激活,以局部皮肤刺激为起始点,引发全身性系统性自身免疫反应。相较于Pristane而言,IMQ诱导的小鼠模型发病相对较快,造模时间短,但其全身症状可能没有Pristane诱导模型全面和严重。

基于上述原理,南模生物通过肾切+Pristane+IMQ诱导构建了SLE模型,并且在不同品系(hCD3EDG/hCD19,BALB/c等)中进行了表型验证,该模型发病快,大大缩短了造模时间,表型明显,可用于SLE抗体类药物的药效评价。部分数据如下:

验证数据:


  • IMQ+Pristane+肾切诱导的BALB/c小鼠SLE模型及药效评价

Fig.1 IMQ and Pristane induce nephrectomy Balb/c mice SLE model. (A) Body weight. (B) Body weight change.

Fig.2 Serum anti-dsDNA IgG Ab of IMQ and Pristane induce nephrectomy Balb/c mice SLE model.

Fig.3 IMQ and Pristane induce nephrectomy Balb/c mice SLE model. (A) mCD45+ cells in live cells proportion. (B) mCD20+ cells in live cells proportion. (C) mCD20+ cells in mCD45+ cells proportion.

Fig.4 IMQ and Pristane induce nephrectomy Balb/c mice SLE model. (A) Urine Albumin. (B) Urine Creatinine. (C) UACR (Albumin to creatinine ratio).

Fig.5 IMQ and Pristane induce nephrectomy Balb/c mice SLE model. (A) Spleen index. (B) Kidney index.

Fig.6 IMQ and Pristane induce nephrectomy Balb/c mice SLE model. (A) Representative H&E staining. (B) Histopathology score.

Fig.7 IMQ and Pristane induce nephrectomy Balb/c mice SLE model. (A) mIgG IHC staining. (B) % mIgG positive cells.

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  • IMQ+Pristane+肾切诱导的hCD3EDG/hCD19(BABL/c)人源化小鼠SLE模型及Cyclophosphamide药效评价

Fig.1 IMQ and Pristane induce nephrectomy hCD3EDG/hCD19 mice SLE model. (A) Body weight. (B) Body weight change.

Fig.2 IMQ and Pristane induce nephrectomy hCD3EDG/hCD19 mice SLE model. (A) Serum BUN. (B) Serum CRE. (*P<0.05, **P<0.01 Vs Group2)

Fig.3 IMQ and Pristane induce nephrectomy hCD3EDG/hCD19 mice SLE model. (A) Serum anti-dsDNA IgG Ab on Day 28. (B) Serum anti-dsDNA IgG Ab on Day 68.

Fig.4 IMQ and Pristane induce nephrectomy hCD3EDG/hCD19 mice SLE model. (A) mCD45+ cells in live cells proportion. (B) mCD20+ cells in live cells proportion. (C) mCD20+ cells in mCD45+ cells proportion.

Fig.5 IMQ and Pristane induce nephrectomy hCD3EDG/hCD19 mice SLE model. (A) Urine Albumin. (B) Urine Creatinine. (C) UACR (Albumin to creatinine ratio). (*P<0.05,**P<0.01 Vs Group2)

Fig.6 IMQ and Pristane induce nephrectomy hCD3EDG/hCD19 mice SLE model. (A) Spleen photo and Kidney photo. (B) Spleen index and Kidney index.  (**P<0.01 Vs Group2)

Fig.7 IMQ and Pristane induce nephrectomy hCD3EDG/hCD19 mice SLE model. (A) Representative H&E images in SLE model. (B)Histopathology score. (*P<0.05 Vs Group2)

Fig.8 IMQ and Pristane induce nephrectomy hCD3EDG/hCD19 mice SLE model. (A) Representative IHC images in SLE model. (B) % mIgG positive cells.

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  • IMQ+Pristane+肾切诱导的hCD3EDG/hCD19(BALB/c)人源化小鼠SLE模型及Blinatumomab药效评价

Fig.1 IMQ and Pristane induce nephrectomy hCD3EDG/hCD19 mice SLE model. (A) Serum anti-dsDNA IgG Ab. (B) Urine Albumin. (C) Urine Creatinine. (D) Albumin to creatinine ratio.

Fig.2 IMQ and Pristane induce nephrectomy hCD3EDG/hCD19 mice SLE model. (A) Representative H&E images in SLE model. (A) Representative IHC images in SLE model. (C)Histopathology score. (D) % mIgG positive cells.

Fig.3 IMQ and Pristane induce nephrectomy hCD3EDG/hCD19 mice SLE model. Flow cytometric quantification of lymph (A) mCD45+, (B) hCD3+, (C) mCD4+, (D) mCD8+, (E) Treg cells, (F) hCD19+ B cells, (G) Dendritic cells (DC), and (H) mCD11b+ myeloid cells.

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人源化SLE模型


人源化SLE模型是将SLE患者的人外周血单核细胞(PBMC)转移到免疫缺陷小鼠中。该模型因其重建了人源免疫系统,可帮助更好地理解人类SLE的特征,在评估靶向人源分子的生物制剂时具有独特的优势,可用于抗体,小分子等药物的临床前测试,加速转化研究。部分数据如下:

验证数据:


  • SLE患者来源的PBMC诱导的M-NSG小鼠SLE模型及药效评价

Fig1. The model of systemic lupus erythematosus induced by SLE-PBMCs in M-NSG mice. (A) Body weight curve. (B) Anti-dsDNA IgG curve. (C) Renal index. (D) Proportion of human CD45+ cells among all CD45+ cells 14 days after immune reconstitution.

Fig2. The efficacy of Blinatumomab on SLE-PBMC induced SLE model in M-NSG mice. (A–H) Changes in the numbers of various immune cells in peripheral blood 7–28 days after immune reconstitution. (I) Time course of anti-dsDNA IgG. (J) Renal index. The results indicate that the monoclonal antibody blinatumomab significantly reduced the number of immune cells, anti-dsDNA IgG levels and the renal index in the SLE-PBMC-induced systemic lupus erythematosus model.

南模生物SLE相关靶点人源化小鼠模型

除上述模型外,南模生物还可提供SLE相关靶点人源化小鼠模型,助力新药开发。部分相关品系如下表:

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如您有相关需求,欢迎拨打400-728-0660或者于微信公众号南模生物SMOC在线咨询,我们的专业团队将竭诚为您服务!


相关阅读

自身免疫疾病及人源化靶点汇总

TL1A:自免潜力靶点,IBD破局者!

CD3/CD19自免双抗研发,这些关键小鼠模型少不了

CD3/CD19/BCMA 从肿瘤免疫到自身免疫性疾病的多面利器

药靶百科|IL-2

Reference:

[1] Dai X, Fan Y, Zhao X. Systemic lupus erythematosus: updated insights on the pathogenesis, diagnosis, prevention and therapeutics. Signal Transduct Target Ther. 2025 Mar 17;10(1):102. doi: 10.1038/s41392-025-02168-0. PMID: 40097390.

关于我们

上海南方模式生物科技股份有限公司(Shanghai Model Organisms Center, Inc.,简称"南模生物"),成立于2000年9月,是一家上交所科创板上市高科技生物公司(股票代码:688265),始终以编辑基因、解码生命为己任,专注于模式生物领域,打造了以基因修饰动物模型研发为核心,涵盖多物种模型构建、饲养繁育、表型分析、药物临床前评价等多个技术平台,致力于为全球高校、科研院所、制药企业等客户提供全方位、一体化的基因修饰动物模型产品解决方案。




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