Mouse Models for Experimental Autoimmune Hepatitis: Limits and Chances

Abstract

The difficulty in studying human autoimmune hepatitis (AIH) is usually the late time-point of diagnosis which is followed by long-standing immunosuppression and the fact that human immune responses can usually only be studied in peripheral blood. Therefore, animal models with defined onset of AIH and, ideally, a positive impact of standard therapeutic interventions are key to understanding the disease and its pathophysiology, and providing a platform for new therapy options or better prevention. For over a century, the lack of a reliable model with a chronic immune response against hepatocytes has been a key problem in AIH research. Initial attempts to break tolerance against liver tissue resulted in mild and transient hepatitis. Many transgenic models demonstrated different aspects of liver-specific immune regulation. The fate of liver-specific T cells is under intense research and many mechanisms have demonstrated ignorance, anergy, deletion or TCR downregulation. Furthermore, these studies defined a role of professional antigen-presenting cells and especially of liver sinusoidal cells. Other models have shown the mechanism of T cell activation in liver and the interaction of adaptive and innate immune cells. Most recently, some approaches have been made to establish models of chronic AIH resembling human disease. These attempts might open new research chances to study AIH onset and its pathophysiology, and they might result in new options for therapy and prevention research.

Medullary thymic epithelial cell depletion leads to autoimmune hepatitis

“…The observation that 10%-15% of patients with APECED (the result of impaired AIRE function and antigen expression in mTECs) develop AIH (59, 60) provides further support for impaired antigen presentation and mTEC function in the pathogenesis of AIH. Therefore, despite the existence of several mouse models of AIH involving chemically induced or liver-intrinsic perturbations of hepatic immune responses (25,54,61), we believe that the Traf6ΔTEC mouse represents a relevant model by which to study the pathogenic mechanisms leading to development of this disease and explore new therapeutic approaches. Further characterization of the Traf6ΔTEC mouse model can not only improve our understanding of the pathophysiology of AIH, but may also lead to a broader understanding of how liver tolerance is established and maintained, with wider impact on other liver autoimmune diseases and liver transplantation.…”

“…It is well known that transplanted livers are less frequently rejected than other solid organ transplants (50)(51)(52)(53). In addition, liver autoimmune diseases like AIH develop with lower frequency compared with other autoimmune conditions, for example, type 1 diabetes and multiple sclerosis (54). Although the causes of AIH remain unknown, current models of AIH development propose that hepatitis development and ensuing tissue damage is orchestrated by naive CD4 + T lym- Autoantibodies and plasma cells.…”

Animal models of chronic liver diseases

“…Therefore, convenient animal models of AIH are required to increase our knowledge of the disease and to explore new drugs for improved therapy. Such models representing AIH have recently been described in detail (57,76), and, therefore, we just highlight here the most representative ones and some new approaches.…”

Natural killer T (NKT) cells in autoimmune hepatitis

“…Different T cell populations play a pivotal role in these processes. Among the liver-specific tolerogenic immune mechanisms the induction of T cell tolerance or the generation of regulatory T cells due to the cross-presentation of antigens by liver sinusoidal cells, T cell apoptosis mediated by hepatic stellate cells and the inactivation of T cells by antigenic priming havebeen discussed [1]. In contrast, altered pathways of T cell survival and antigen presentation [2] as well as modified cytokine milieus or costimulatory signals [3] might drive tissue damage due to an aberrant activation of the immune system.…”