Abstract
A key aspect of the immune response to adenovirus (Ad) gene therapy is the generation of a cytotoxic T-cell (CTL) response. To better understand the genetic network underlying these events, 20 strains of C57BL/6 × DBA/2 (BXD) recombinant inbred (RI) mice were administered with AdLacZ and analyzed at days 7, 21, 30, and 50 for liver β-galactosidase (LacZ) expression and CTL response. Sera levels of interferon gamma (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6) were analyzed at different times after AdLacZ. There was a distinct strain-dependent expression of LacZ, which was strongly correlated with the CTL response. Among the five BXD RI strains that exhibited significantly prolonged LacZ expression, four also exhibited a marked defect in the production of Ad-specific CTL. There was a strong correlation between the sera levels of IFN-γ, TNF-α, and IL-6, but cytokine responses were not significantly correlated with LacZ expression or the CTL response. Quantitative trait loci regulating LacZ on day 30 were found on chromosome (Chr) 19 (33 cM) and Chr 15 (42.8 cM). Cytotoxicity mapped to Chr 7 (41.0 and 57.4–65.2 cM), Chr 15 (61.7 cM), and Chr X (27.8 cM). IFN-γ production mapped to Chr 18 (22, 27, and 32 cM) and Chr 11 (64.0 cM). TNF-α and IL-6 production mapped to Chr 6 (91.5 cM) Chr 9 (42.0 cM) and Chr 8 (52 and 73.0 cM). These results indicate that different strains of mice exhibit different pathways for effective clearance of AdLacZ depending on genetic polymorphisms and interactions at multiple genetic loci.
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Acknowledgements
We thank Ms Carol Humber for excellent secretarial work. This work was supported by NIH Grants R01 AG 16653, N01 AR 6-2224, RO1 AI 42900, and CA 20408, and a Birmingham VAMC Merit Review Grant. Huang-Ge Zhang is a recipient of Arthritis Foundation Investigator Award.
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Zhang, HG., Hsu, HC., Yang, PA. et al. Identification of multiple genetic loci that regulate adenovirus gene therapy. Gene Ther 11, 4–14 (2004). https://doi.org/10.1038/sj.gt.3302136
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DOI: https://doi.org/10.1038/sj.gt.3302136