title: Use of a liver-specific promoter reduces immune response to the transgene in adenoviral vectors.
abstract: Previous studies using adenoviral (Ad) vectors expressing human alpha1-antitrypsin (hAAT) under the control of ubiquitous promoters (RSV, mPGK) elicited the production of antibodies to hAAT in some mouse strains (C3H/HeJ and BALB/c) but not in others (C57BL/6J). In contrast, when a helper-dependent Ad vector (AdSTK109) with all viral coding sequences deleted and expressing hAAT from human genomic DNA with the endogenous promoter was used, C3H/HeJ mice failed to develop antibodies and demonstrated long-term expression. These results suggested that promoter choice and/or properties of the vector itself might influence the host immune response to the transgene product. Direct comparison of first-generation vectors expressing the hAAT cDNA from a ubiquitous mouse PGK promoter rather than from a liver-specific mouse albumin promoter demonstrated that an antibody response to hAAT occurred with the mPGK promoter but not with the albumin promoter in C3H/HeJ mice. As expected, neither vector elicits an antibody response in C57BL/6J mice. Coinjection of the two first-generation vectors containing the mPGK and albumin promoter in C3H/HeJ mice induced an antibody response with resulting loss of detectable hAAT from the sera of the injected mice in 3-4 weeks. From these data, we conclude that under certain conditions, the choice of promoter with its associated liver-specific expression can modulate the host immune response to the transgene independent of viral backbone.
authors.affiliation: Department of Molecular and Human Genetics, Baylor College of Medicine and Houston, TX 77030, USA.
authors.forename: L
authors.initials: L
authors.lastname: Pastore
authors.forename: N
authors.initials: N
authors.lastname: Morral
authors.forename: H
authors.initials: H
authors.lastname: Zhou
authors.forename: R
authors.initials: R
authors.lastname: Garcia
authors.forename: R J
authors.initials: RJ
authors.lastname: Parks
authors.forename: S
authors.initials: S
authors.lastname: Kochanek
authors.forename: F L
authors.initials: FL
authors.lastname: Graham
authors.forename: B
authors.initials: B
authors.lastname: Lee
authors.forename: A L
authors.initials: AL
authors.lastname: Beaudet
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000906:Antibodies / Q000097:blood; D004279:DNA, Viral / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D005822:Genetic Vectors; D006378:Helper Viruses / Q000235:genetics; D006801:Humans; D008099:Liver / Q000201:enzymology / Q000473:pathology; D051379:Mice; D008809:Mice, Inbred C3H; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic; D019076:Transgenes / Q000235:genetics / Q000276:immunology; D000515:alpha 1-Antitrypsin / Q000235:genetics / Q000276:immunology / Q000378:metabolism
chemical_list: D000906:Antibodies; D004279:DNA, Viral; D000515:alpha 1-Antitrypsin