title: Cytotoxic immune response blunts long-term transgene expression after efficient retroviral-mediated hepatic gene transfer in rat.
abstract: Vectors derived from oncoretroviruses can transduce a small proportion of hepatocytes when injected in the regenerating liver. Transgene expression may be sustained for months without immune response. In striking contrast, we observed a rapid extinction when the intravenous injection of a high input of nuclear beta-galactosidase (beta-gal) expression vector, one day after partial hepatectomy, led to a significant proportion of transduced cells in the liver. Extinction was associated with liver inflammation on tissue sections and appearance of antibodies against the transgene product, while vector genomes became undetectable in liver tissue by PCR. These observations suggested the elimination of transduced cells by an immune response. Transgenic rats tolerant for cytoplasmic beta-gal, or normal rats depleted in CD8 T lymphocytes, steadily expressed the beta-gal vector. In the spleen of normal rats, we detected cytotoxic cells directed against cells expressing beta-gal after the injection of the beta-gal vector. In jaundiced Gunn rats deficient in bilirubin glucuronosyl transferase (BGT1) and treated with a human BGT1 cDNA expression vector, we observed the same kinetics of extinction as well as the appearance of anti-BGT1 antibodies. This study demonstrates that retrovirus-mediated gene transfer may induce cytotoxic T lymphocytes specifically directed against transgene-expressing cells.
authors.affiliation: Laboratoire de Thérapie Génique INSERM 0105, Nantes, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Aubert
authors.forename: Séverine
authors.initials: S
authors.lastname: Ménoret
authors.forename: Estelle
authors.initials: E
authors.lastname: Chiari
authors.forename: Virginie
authors.initials: V
authors.lastname: Pichard
authors.forename: Sophie
authors.initials: S
authors.lastname: Durand
authors.forename: Laurent
authors.initials: L
authors.lastname: Tesson
authors.forename: Philippe
authors.initials: P
authors.lastname: Moullier
authors.forename: Ignacio
authors.initials: I
authors.lastname: Anegon
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ferry
mesh_terms: D000818:Animals; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression / Q000276:immunology; D014453:Glucuronosyltransferase / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051381:Rats; D011911:Rats, Gunn; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D012190:Retroviridae / Q000276:immunology; D013154:Spleen / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D014161:Transduction, Genetic; D019076:Transgenes; D001616:beta-Galactosidase / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology
chemical_list: D011993:Recombinant Fusion Proteins; C019787:bilirubin glucuronoside glucuronosyltransferase; D014453:Glucuronosyltransferase; D001616:beta-Galactosidase