Experimental autoimmune cholangitis: a mouse model of immune-mediated cholangiopathy

Background: Primary biliary cirrhosis (PBC) is characterised by intra-hepat ic immune-mediated cholangiopathy (non-suppurative destructive cholangitis (NSDC)). Although auto-reactive immune responses against pyruvate dehydroge nase complex (PDC) have been characterised in PBC, the lack of an animal mo del of the disease has limited study of the mechanisms of disease induction and the development of novel approaches to therapy. Aims: To develop and v alidate a mouse model of immune-mediated cholangiopathy relevant for future use in the study of the aetio-pathogenesis and therapy of PBC. Methods: Fe male SJL/J, C57BL/6, NOD and BALB/c mice were sensitised with PDC, its puri fied E2/E3BP component, and a PDC-E2 derived peptide p163 (a dominant T-cel l epitope in humans) in complete Freund's adjuvant (CFA). Morphological cha nges were assessed under light microscopy by a hepatic histopathologist bli nded to the experimental details. Antibody responses to PDC were studied by ELISA and PDC inhibition assay. Results: An initial series of experiments was performed to survey the susceptibility of female mice of a range of str ains to the induction of NSDC by i.p. sensitisation with PDC, PDC-E2/E3BP o r p163 in CFA. Although each animal showed a specific antibody response fol lowing sensitisation, it was found that NSDC development (assessed at 30 we eks post-sensitisation) was restricted to SJL/J mice following sensitisatio n with any of the mitochondrial antigen preparations. A subsequent series o f experiments was performed to examine the specificity and aetiology of thi s disease. Significant bile duct lesions were only seen in SJL/J animals fo llowing sensitisation with CFA containing PDC, and were absent from CFA onl y 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. Conclusions: We have described a model of experime ntal autoimmune cholangitis (EAC) with immunological (anti-PDC antibodies) and histological (immune-mediated cholangiopathy) features suggestive of PB C. This model may be useful in further defining the role of self-tolerance breakdown in the development of this condition.