Immunotherapy directed against alpha-fetoprotein results in autoimmune liver disease during liver regeneration in mice

Background & Aims. Priming immune responses against alpha -fetoprotein (AFP ) highly expressed in the majority of hepatocellular carcinomas results in significant antitumoral T-cell responses. Liver regeneration in humans and mice, however, is also associated with increased AFP expression. Therefore, we evaluated the risk of AFP-directed immunotherapeutic approaches to indu ce autoimmunity against the regenerating liver. Methods: Mice were immunize d with DNA encoding mouse AFP. For induction of liver regeneration, partial hepatectomy was performed and mice were monitored by serial histopathologi c examinations and measurements of serum ALT activities (U/L), and by deter mination of the kinetics of AFP-specific T-cell responses. Results: Livers of AFP immune mice without partial hepatectomy were characterized by minor lymphocytic infiltrations without transaminase elevations. By contrast, a s ignificant hepatocyte damage was observed in regenerating liver that correl ated well with the number of AFP-specific CD8(+) T cells, the activity of l iver regeneration, and the level of AFP synthesis. Autoimmune liver damage was mediated by CD4(+) T cell-dependent CD8+ cytotoxic T lymphocytes. Concl usions; These results show that priming of T-cell responses against shared tumor-specific self antigens may be accompanied by induction of autoimmunit y dependent on the level of expression of the self antigen and have importa nt implications for the development of antitumoral vaccines targeted agains t antigens that are not strictly tumor-specific.