A transgenic mouse with β-Galactosidase as a fetal liver self-antigen for immunotherapy studies

Background/Aims: To optimise vaccination strategies for immunotherapy in the liver, we have generated a line of transgenic mice expressing beta-Galactosidase downstream of the alpha-fetoprotein promoter (AFP/beta Gal). Methods: beta Gal expression was documented by qRT-PCR, enzyme activity and immunohistochemistry. beta Gal-specific CD8+ T-cell activation in mice immunised with various vectors was measured by interferon-gamma ELISpot. Results:Like AFP, beta Gal expression was detected in fetal hepatocytes and disappeared around birth. In adult mice, a CD8+ T-cell response to beta Gal was observed after immunisation with beta Gal adenovirus or plasmid DNA but not with beta Gal protein or after retroviral infection. When beta Gal was re-expressed in adult hepatocytes, immunisation with beta Gal adenovirus triggered T-cell mediated elimination of beta Gal-expressing hepatocytes. However, the response was weaker than in AFP/beta Gal animals in which beta Gal was only present around birth. Conclusions: In AFP/beta Gal mice, beta Gal is a fetal liver self-antigen. Interestingly, the basal tolerance to beta Gal displayed by these animals is increased during liver re-expression of the self-antigen in adulthood. Adenoviral immunisation allows complete elimination of beta Gal-expressing hepatocytes in spite of this increased peripheral tolerance. These results highlight the importance of tolerance against self-antigens and validate the AFP/beta Gal mice as a good background to test immunotherapy strategies in hepatocarcinogenesis models. (C) 2007 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.