A new animal model of chronic autoimmune hepatitis mediated by the adaptive immune system

Abstract

Progress in our understanding of autoimmune hepatitis (AIH) has been hampered by the lack of suitable animal models. Here we 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 a self-limited acute phase of liver destruction with elevated levels of transaminases we saw chronic evolving hepatic autoimmune reactions at 12 weeks, which were not seen after infection with control virus. 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. The induction of chronic AIH was dependent on the genetic background of the mice. Non-obese diabetic (NOD) mice showed autoimmunity within the liver using viral constructs expressing FTCD, an important auto-antigen in AIH type II. Surprisingly CYP2D6 as well as soluble liver antigen (SLA) did not show any chronic hepatic immune reaction. 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. The model might open new therapeutic options to treat the disease.