Requirements and Challenges of a Preclinical Autoimmune Hepatitis Mouse Model

Abstract

Autoimmune hepatitis (AIH) is a chronic autoimmune inflammation of the liver usually requiring life-long immunosuppression. Steroids and azathioprin are the standard therapy, but the therapy is accompanied by strong side effects. Due to the fact that AIH is often recognized during late course of disease, it is difficult to obtain knowledge about the immunological mechanisms responsible for initiation of the disease. Current AIH models were helpful for understanding and modulating liver immune responses, but are not suited to study mechanisms in chronic AIH or to develop new therapies. While transgenic AIH models deal with short-term hepatitis, models with natural antigens are either self-limited or have unknown target antigens. Therefore, new animal models with defined onset of AIH and a standard course of the disease are essential for a more defined understanding of the disease and its pathophysiology. To obtain a preclinical platform for new therapeutic approaches or to be able to prevent onset of AIH, a positive impact of conventional standard therapeutic interventions in the model would be helpful. For decades, AIH research has lacked such a reliable preclinical model with chronic immune response against the liver. Initial results in breaking tolerance against hepatocytes have only led to mild and transient hepatitis. Transgenic models were helpful in understanding different aspects for hepatic immune regulation. Nowadays, the fate of T cells, especially CD8+ T cells, is the focus of research. Especially ignorance, anergy, deletion or TCR downregulation of T cells are mechanisms of tolerance against hepatic antigens. Furthermore, the importance of professional antigen-presenting cells and particularly liver sinusoidal cells in liver tolerance has been demonstrated in many studies. Other models have shown the mechanism of interaction of adaptive and innate immune cells in the liver. Recently, approaches have been made to establish AIH models reflecting the situation in AIH patients. This will allow new studies in the field and will provide an opportunity to study the onset and pathophysiology of AIH. Furthermore, these models will try new options for therapeutic approaches and might show options of how to prevent onset of disease.