Use of a liver-specific promoter reduces immune response to the transgene in adenoviral vectors

• Published in: Human gene therapy Vol. 10; no. 11; p. 1773
• Main Authors: Pastore, L, Morral, N, Zhou, H, Garcia, R, Parks, R J, Kochanek, S, Graham, F L, Lee, B, Beaudet, A L
• Format: Journal Article
• Language: English
• Published: United States 20.07.1999
• Subjects: Adenoviridae - genetics; alpha 1-Antitrypsin - genetics; alpha 1-Antitrypsin - immunology; alpha 1-Antitrypsin - metabolism; Animals; Antibodies - blood; DNA, Viral - analysis; Enzyme-Linked Immunosorbent Assay; Genetic Vectors; Helper Viruses - genetics; Humans; Liver - enzymology; Liver - pathology; Mice; Mice, Inbred C3H; Polymerase Chain Reaction - methods; Promoter Regions, Genetic; Transgenes - genetics; Transgenes - immunology
• ISSN: 1043-0342
• DOI: 10.1089/10430349950017455

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.