Models of Autoimmune Hepatitis

Abstract

Several murine models of autoimmune hepatitis (AIH) have been described in the course of investigating the immune mechanisms involved in the development of AIH. However, those models have lacked the characteristics of human AIH, such as hypergammaglobulinemia and production of circulating autoantibodies. In contrast, we have developed mouse models of spontaneous AIH with hypergammaglobulinemia and ANA production. Immune dysregulation by a concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling induces different phenotypes of AIH in mice with different genetic backgrounds. Using these models, we have shown that the spleen is the induction site for AIH, that follicular helper T cells constitute the T-cell subset responsible for induction, and that the CCR6–CCL20 axis is crucial for the migration of dysregulated T cells from the spleen into the liver. As fatal AIH progresses, the CXCR3–CXCL9 axis is crucial for the migration of T helper 1 cells and effector CD8+ T cells into the liver, causing fatal damage. Dendritic-cell-derived IL-18 is critical for differentiation of CXCR3-expressing Th1 cells and CD8+ effector T cells in the spleen. In addition, we have found some clues that should help in overcoming the therapeutic insufficiency of corticosteroids for AIH patients.