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 β-Galactosidase downstream of the alpha-fetoprotein promoter (AFP/βGal). Methods βGal expression was documented by qRT-PCR, enzyme activity and immunohistochemistry. βGal-specific CD8+ T-cell activation in mice immunised with various vectors was measured by interferon-γ ELISpot. Results Like AFP, βGal expression was detected in fetal hepatocytes and disappeared around birth. In adult mice, a CD8+ T-cell response to βGal was observed after immunisation with βGal adenovirus or plasmid DNA but not with βGal protein or after retroviral infection. When βGal was re-expressed in adult hepatocytes, immunisation with βGal adenovirus triggered T-cell mediated elimination of βGal-expressing hepatocytes. However, the response was weaker than in AFP/βGal animals in which βGal was only present around birth. Conclusions In AFP/βGal mice, βGal is a fetal liver self-antigen. Interestingly, the basal tolerance to βGal displayed by these animals is increased during liver re-expression of the self-antigen in adulthood. Adenoviral immunisation allows complete elimination of βGal-expressing hepatocytes in spite of this increased peripheral tolerance. These results highlight the importance of tolerance against self-antigens and validate the AFP/βGal mice as a good background to test immunotherapy strategies in hepatocarcinogenesis models.