Z Gastroenterol 2009; 47 - P342
DOI: 10.1055/s-0029-1241590

Immunopathology in a novel model of chronic AIH

K Fischer 1, M Hardtke-Wolenski 1, MP Manns 1, E Jaeckel 1
  • 1Medizinische Hochschule Hannover, Gastroenterologie, Hepatologie & Endokrinologie, Hannover, Germany

Progress in our understanding of autoimmune hepatitis (AIH) has been hampered by the lack of suitable animal models.We have developed a strategy to break tolerance of a negatively selected, wild-type T cell repertoire by combining a self limited infection providing a danger signal together with modified liver self-antigens into mice. To this end we generated replication-deficient adenoviral constructs expressing common autoantigens of human AIH showing homology up to 80% with the murine proteins. Following an acute phase of liver destruction with increasing levels of transaminases two weeks after intravenous injection of the virus, we could show chronic evolving hepatic autoimmune reactions after twelve weeks. Chronic liver disease was confirmed by consistent leukocyte infiltrates and antigen-specific autoantibodies within the sera. Immunofluorescent staining of liver sections revealed that CD4 T cells are more abundant than CD8 T cells in these liver infiltrates. Control experiments with expression vectors devoid of viral components did not result in any hepatic reaction after the acute viral infection had been cleared. Furthermore chronic AIH was not induced in FVB mice. However we detected autoimmunity within the liver of non-obese diabetic (NOD) mice which received viral constructs expressing FTCD, an important auto-antigen in AIH type II. Surprisingly the more important AIH type II auto-antigen CYP2D6 as well as the type III soluble liver antigen (SLA) did not result in any chronic hepatic immune reaction. This strain and antigen-specificity of murine AIH supports the notion that autoimmunity develops in genetically predisposed individuals. To identify the leukocyte populations involved in hepatitis within our model we isolated liver-specific leukocytes of hepatitis-bearing mice and analysed these by flow cytometry as well as by a new technique of microimmunology called iterative Slide Based Cytometry (iSBC). Taken together, this murine model of chronic AIH will be significant in the study of liver-specific autoimmunity particularly with regard to the liver-specific immune regulation by different T cell populations. Moreover the novel model might open new therapeutic options to treat the disease.