A transgenic mouse with beta-Galactosidase as a fetal liver self-antigen for immunotherapy studies.
OBJECTIVE
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.
Cany
Jeannette
J
INSERM CIC04, Biothérapies Hépatiques, CHU Hotel Dieu, Nantes F-44000, France.
Avril
Audrey
A
Pichard
Virginie
V
Aubert
Dominique
D
Ferry
Nicolas
N
Conchon
Sophie
S
D000256:Adenoviridae / Q000235:genetics; D000375:Aging / Q000378:metabolism; D000818:Animals; D000917:Antibody Formation; D001324:Autoantigens / Q000627:therapeutic use*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D004247:DNA / Q000627:therapeutic use; D005333:Fetus / Q000378:metabolism; D005822:Genetic Vectors; D022781:Hepatocytes / Q000378:metabolism; D007114:Immunization; D007167:Immunotherapy / Q000379:methods*; D008099:Liver / Q000196:embryology* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D010957:Plasmids / Q000627:therapeutic use; D011401:Promoter Regions, Genetic; D000509:alpha-Fetoproteins / Q000235:genetics; D001616:beta-Galactosidase / Q000276:immunology* / Q000378:metabolism / Q000627:therapeutic use*
D001324:Autoantigens; D000509:alpha-Fetoproteins; D004247:DNA; D001616:beta-Galactosidase