Effects and regulation of autoreactive CD8+ T cells in a transgenic mouse model of autoimmune hepatitis

Gastroenterology
Mario ZierdenHans-Peter Dienes

Abstract

Autoimmune hepatitis (AIH) is a chronic inflammatory liver disease of unknown etiology. Autoreactive T cells are thought to mediate liver injury, but the pathogenesis of AIH is poorly understood because of the lack of suitable animal models. We established a mouse model to investigate liver-specific T-cell responses and assess the effects and regulation of autoreactive CD8(+) T cells in the pathogenesis of AIH. We generated transgenic mice expressing the influenza virus hemagglutinin (HA) autoantigen under control of mouse albumin regulatory elements and alpha-fetoprotein enhancers (Alb) specifically in the liver (Alb-HA mice); they were crossed with mice that express a specific T-cell receptor (TCR) (CL4-TCR). CL4-TCR transgenic CD8(+) T cells were also adoptively transferred into Alb-HA mice. We investigated immunologic mechanisms of CD8(+) T cell-induced liver damage and of counteracting peripheral tolerance. The double-transgenic mice (Alb-HA/CL4-TCR) spontaneously developed chronic, autoimmune-mediated hepatitis, characterized by necroinflammatory lesions, hepatic fibrosis, and increased levels of aminotransferase; these features resembled those of AIH. Interestingly, most liver-infiltrating, HA-specific CD8(+) T cells had...Continue Reading

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