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

Authors
  • Fuchs, Sina1
  • Bayer, Monika1
  • Taubert, Richard2
  • Manns, Michael P2
  • Pfeilschifter, Josef M1
  • Christen, Urs1
  • Hintermann, Edith1
  • 1 Pharmazentrum Frankfurt / ZAFES, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany. , (Germany)
  • 2 Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. , (Germany)
Type
Published Article
Journal
Liver international : official journal of the International Association for the Study of the Liver
Publication Date
Dec 01, 2019
Volume
39
Issue
12
Pages
2330–2340
Identifiers
DOI: 10.1111/liv.14183
PMID: 31225929
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

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. 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. 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. 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. © 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

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