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A transgenic mouse with beta-Galactosidase as a fetal liver self-antigen for immunotherapy studies
Jeannette Cany1, Audrey Avril, Virginie Pichard
1INSERM CIC04, Biothérapies Hépatiques, CHU Hotel Dieu, Nantes F-44000, France.
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/betaGal).
Methods:
betaGal expression was documented by qRT-PCR, enzyme activity and immunohistochemistry. betaGal-specific CD8+ T-cell activation in mice immunised with various vectors was measured by interferon-gamma ELISpot.
Results:
Like AFP, betaGal expression was detected in fetal hepatocytes and disappeared around birth. In adult mice, a CD8+ T-cell response to betaGal was observed after immunisation with betaGal adenovirus or plasmid DNA but not with betaGal protein or after retroviral infection. When betaGal was re-expressed in adult hepatocytes, immunisation with betaGal adenovirus triggered T-cell mediated elimination of betaGal-expressing hepatocytes. However, the response was weaker than in AFP/betaGal animals in which betaGal was only present around birth.
Conclusions:
In AFP/betaGal mice, betaGal is a fetal liver self-antigen. Interestingly, the basal tolerance to betaGal displayed by these animals is increased during liver re-expression of the self-antigen in adulthood. Adenoviral immunisation allows complete elimination of betaGal-expressing hepatocytes in spite of this increased peripheral tolerance. These results highlight the importance of tolerance against self-antigens and validate the AFP/betaGal mice as a good background to test immunotherapy strategies in hepatocarcinogenesis models.
