Effects of adenovirus-induced hepatocyte damage on chronic bile duct inflammation in a sclerosing cholangitis mouse model.

Background & Aims: Four major autoimmune diseases target the liver. They develop because of bile duct destruction, leading to chronic cholestasis or result from hepatocyte damage like autoimmune hepatitis (AIH). Interestingly, some patients simultaneously show features of both cholangitis and AIH. Our goal was to mimic such concurrent characteristics in a mouse model that would help deciphering mechanisms possibly involved in an inflammatory crosstalk between cholestatic disease and hepatitis.

Methods: Mdr2 mice, which spontaneously develop sclerosing cholangitis because of accumulation of toxic bile salts, were infected with adenovirus (Ad) encoding human Cytochrome P4502D6 (hCYP2D6), the major target autoantigen in type-2 AIH, to trigger hepatocyte injury. Wild type FVB mice were controls.

Results: Resulting Ad-Mdr2 mice presented with cholangitis, fibrosis and cellular infiltrations that were higher than in Mdr2 or Ad-FVB mice. Increased levels of anti-neutrophil cytoplasmic antibodies but similar anti-hCYP2D6 antibody titres were detected in Ad-Mdr2 compared to Mdr2 and Ad-FVB mice respectively. IFNγ-expressing hCYP2D6-specific CD4 T cells declined, whereas hCYP2D6-specific CD8 T cells increased in Ad-Mdr2 compared to Ad-FVB mice. The overall T cell balance in Ad-Mdr2 mice was a combination of a type 17 T cell response typically found in Mdr2 mice with a type 1 dominated T cell response characteristic for Ad-FVB mice. Simultaneously, the type 2 T cell compartment was markedly reduced.

Conclusions: Experimental hepatitis induction in a mouse with sclerosing cholangitis results in a disorder which represents not simply the sum of the individual characteristics but depicts a more complex entity which urges on further analysis.