原发性胆汁性胆管炎动物模型的研究进展

徐雅菲; 赵志斌; 廉哲雄

doi:10.3969/j.issn.1001-5256.2021.10.006

原发性胆汁性胆管炎动物模型的研究进展

DOI: 10.3969/j.issn.1001-5256.2021.10.006

1.
华南理工大学医学院，广州 510006
2.
广东省人民医院，广州 510000

详细信息

通信作者:
廉哲雄，zxlian@scut.edu.cn

中图分类号: R575.22
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- 被引次数: 0
出版历程
- 收稿日期: 2021-07-20
- 录用日期: 2021-08-25
- 出版日期: 2021-10-20

Research advances in animal models of primary biliary cholangitis

1.
School of Medicine, South China University of Technology, Guangzhou 510006, China
2.
Guangdong Provincial People's Hospital, Guangzhou 510000, China

摘要

摘要: 原发性胆汁性胆管炎(PBC)是由针对肝内中小胆管的自身免疫反应引起的胆汁淤积性肝脏炎症疾病。临床上最具疾病特异性的表现为自身抗线粒体抗体阳性和肝脏组织学上的选择性中小胆管破坏。由于PBC早期临床样本难以获取，构建并优化合适的小鼠模型是研究PBC发病机制的重要手段。了解PBC动物模型的建模原理和在血清学、组织学、细胞学上的疾病特征表现，既有利于加深对PBC疾病的认识，也有助于科学、合理地设计研究方案。
- 自身免疫疾病 /
- 肝硬化, 胆汁性 /
- 疾病模型, 动物
Abstract: Primary biliary cholangitis (PBC) is an inflammatory and cholestatic liver disease caused by autoimmune response targeting the small- and medium-sized intrahepatic bile ducts. The most specific manifestations of this diseases in clinical practice were positive anti-mitochondrial antibody and selective destruction of small- and medium-sized bile ducts based on liver histology. Since it is difficult to obtain the clinical samples of early-stage PBC, the construction and optimization of mouse models is an important method to investigate the pathogenesis of PBC. An understanding of the modeling principles of PBC animal models and disease features in serology, histology, and cytology not only helps to improve the awareness of PBC, but also helps to design scientific and rational research protocols.
- Autoimmune Diseases /
- Liver Cirrhosis, Biliary /
- Disease Models, Animal

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表 1 不同PBC模型特点比较

PBC模型	造模原理	优点	缺点	并发症	主要致病细胞	模型选择建议
dnTGFβRⅡ	T淋巴细胞中的TGFβ信号通路被阻断	模拟了PBC早期的关键血清学、病理学特征	门静脉区未见嗜酸性粒细胞浸润和肉芽肿	炎症性肠病	CD8⁺ T淋巴细胞(PBC)	适于探究PBC早期发病过程
dnTGFβRⅡ	T淋巴细胞中的TGFβ信号通路被阻断	模拟了PBC早期的关键血清学、病理学特征	未见循环IgM的持续升高，而是出现IgA水平升高	炎症性肠病	CD4⁺ T淋巴细胞(结肠炎)	适于探究PBC早期发病过程
ARE-Del^-/-	慢性、持续性表达性IFNγ	明显的性别倾向	检测不到ALP 肝纤维化程度较轻	系统性红斑狼疮	CD4⁺ T淋巴细胞	适于探究PBC的性别差异
NOD.c3c4	NOD模型鼠获得胰岛素依赖性糖尿病抗性	部分小鼠可见嗜酸性粒细胞浸润、上皮样肉芽肿样病变和早期肝纤维化	自身免疫的初始攻击位置与临床不同	肝脏胆道多囊病	CD4⁺ T淋巴细胞和CD8⁺ T淋巴细胞单独均可致病	-
			AMA阳性率较低
			检测不到ALP
			血清中IgM和IgA均升高
Scurfy	Treg细胞完全缺陷	-	全身性的自身免疫性疾病	全身性的自身免疫病	CD8⁺ T淋巴细胞	-
Scurfy	Treg细胞完全缺陷	-	寿命只有4周左右	全身性的自身免疫病	CD8⁺ T淋巴细胞	-
IL-2Rα^-/-	Treg细胞减少	-	没有肉芽肿和嗜酸性粒细胞浸润	严重贫血	CD8⁺ T淋巴细胞(PBC)	-
				淋巴组织增生性自身免疫病	CD4⁺ T淋巴细胞(结肠炎)
				溃疡性结肠炎	CD4⁺ T淋巴细胞(结肠炎)
IL-2Rα^-/- IL12-p40^-/-	在IL-2Rα^-/-模型的基础上敲除IL-12p40	抑制了IL-2Rα^-/-模型的结肠炎	-	干燥综合征	CD8⁺ T淋巴细胞	适于探究PBC重度炎症及向纤维化发展的发病过程
IL-2Rα^-/- IL12-p40^-/-	在IL-2Rα^-/-模型的基础上敲除IL-12p40	加重了肝门静脉炎症和胆管损伤，并促进其向肝纤维化发展	-	贫血和髓外造血	CD8⁺ T淋巴细胞	适于探究PBC重度炎症及向纤维化发展的发病过程
Ae2a, b^-/-	破坏Cl^-/HCO₃^-跨质膜交换，干扰细胞内pH调控	-	个体差异大	-	-	-
2OA-BSA免疫	用能被AMA识别的半抗原进行长期诱导	可见上皮样肉芽肿样病变	检测不到胆汁淤积酶	-	CD8⁺ T淋巴细胞	适于探究环境因素引起的PBC早期发病过程
2OA-BSA免疫	用能被AMA识别的半抗原进行长期诱导	可见上皮样肉芽肿样病变	不能进展为肝脏纤维化	-	CD8⁺ T淋巴细胞	适于探究环境因素引起的PBC早期发病过程
2OA-poly Ⅰ∶C联合免疫	在2OA-BSA免疫模型的基础上加以病毒RNA模拟物诱导	促进了2OA免疫小鼠的PBC进展	-	-	-	适于探究环境因素引起的PBC发病过程
		可见嗜酸性粒细胞浸润
		部分小鼠出现肝纤维化
注: “-”表示特征不显著或鲜有报道。

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