Jones D E, Palmer J M, Kirby J A, De Cruz D J, McCaughan G W, Sedgwick J D, Yeaman S J, Burt A D, Bassendine M F
Centre for Liver Research, The Medical School, University of Newcastle, Newcastle upon Tyne, UK.
Liver. 2000 Oct;20(5):351-6. doi: 10.1034/j.1600-0676.2000.020005351.x.
Primary biliary cirrhosis (PBC) is characterised by intra-hepatic immune-mediated cholangiopathy (non-suppurative destructive cholangitis (NSDC)). Although auto-reactive immune responses against pyruvate dehydrogenase complex (PDC) have been characterised in PBC, the lack of an animal model of the disease has limited study of the mechanisms of disease induction and the development of novel approaches to therapy.
To develop and validate a mouse model of immune-mediated cholangiopathy relevant for future use in the study of the aetio-pathogenesis and therapy of PBC.
Female SJL/J, C57BL/6, NOD and BALB/c mice were sensitised with PDC, its purified E2/E3BP component, and a PDC-E2 derived peptide p163 (a dominant T-cell epitope in humans) in complete Freund's adjuvant (CFA). Morphological changes were assessed under light microscopy by a hepatic histopathologist blinded to the experimental details. Antibody responses to PDC were studied by ELISA and PDC inhibition assay.
An initial series of experiments was performed to survey the susceptibility of female mice of a range of strains to the induction of NSDC by i.p. sensitisation with PDC, PDC-E2/E3BP or p163 in CFA. Although each animal showed a specific antibody response following sensitisation, it was found that NSDC development (assessed at 30 weeks post-sensitisation) was restricted to SJL/J mice following sensitisation with any of the mitochondrial antigen preparations. A subsequent series of experiments was performed to examine the specificity and aetiology of this disease. Significant bile duct lesions were only seen in SJL/J animals following sensitisation with CFA containing PDC, and were absent from CFA only and un-sensitised controls. Kinetic analysis revealed that this pathology developed slowly, but a high incidence of animals with severe lesions was observed after 30 weeks.
We have described a model of experimental autoimmune cholangitis (EAC) with immunological (anti-PDC antibodies) and histological (immune-mediated cholangiopathy) features suggestive of PBC. This model may be useful in further defining the role of self-tolerance breakdown in the development of this condition.
原发性胆汁性肝硬化（PBC）的特征是肝内免疫介导的胆管病（非化脓性破坏性胆管炎（NSDC））。尽管在PBC中已经明确了针对丙酮酸脱氢酶复合体（PDC）的自身反应性免疫反应，但缺乏该疾病的动物模型限制了对疾病诱导机制和新治疗方法的研究。
建立并验证一种免疫介导的胆管病小鼠模型，以供未来用于研究PBC的病因发病机制和治疗。
用PDC、其纯化的E2/E3BP组分以及一种PDC-E2衍生肽p163（人类中的主要T细胞表位）在完全弗氏佐剂（CFA）中对雌性SJL/J、C57BL/6、NOD和BALB/c小鼠进行致敏。由对实验细节不知情的肝脏组织病理学家在光学显微镜下评估形态学变化。通过酶联免疫吸附测定（ELISA）和PDC抑制试验研究对PDC的抗体反应。
进行了一系列初始实验，以调查一系列品系的雌性小鼠经腹腔注射用CFA中的PDC、PDC-E2/E3BP或p163致敏后诱导NSDC的易感性。尽管每只动物在致敏后都表现出特异性抗体反应，但发现用任何一种线粒体抗原制剂致敏后，NSDC的发展（在致敏后30周评估）仅限于SJL/J小鼠。随后进行了一系列实验以检查该疾病的特异性和病因。仅在用含PDC的CFA致敏后的SJL/J动物中观察到明显的胆管病变，而仅CFA组和未致敏对照组中未出现。动力学分析显示这种病理变化发展缓慢，但在30周后观察到有严重病变的动物发生率很高。
我们描述了一种具有免疫（抗PDC抗体）和组织学（免疫介导的胆管病）特征的实验性自身免疫性胆管炎（EAC）模型，这些特征提示PBC。该模型可能有助于进一步确定自身耐受破坏在这种疾病发展中的作用。
