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Helper-dependent adenovirus vectors elicit intact innate but attenuated adaptive host immune responses in vivo.
J Virol. 2004 Jun; 78(11):5966-72.JV

Abstract

Helper-dependent adenovirus (HD-Ad) vectors with all adenoviral genes deleted mediate very long-term expression of therapeutic transgenes in a variety of animal models of disease. These vectors are associated with reduced toxicity and improved safety relative to traditional early region 1 deletion first-generation Ad (FG-Ad) vectors. Many studies have clearly demonstrated that FG-Ad vectors induce innate and adaptive immune responses in vivo; however, a comprehensive analysis of host immune responses to HD-Ad vectors has not yet been performed. In DBA/2 mice, intravenous injection of HD-Ad vectors encoding LacZ (HD-AdLacZ) or a murine secreted alkaline phosphatase (HD-AdSEAP) induced an early expression of inflammatory cytokine and chemokine genes in the liver, including interferon-inducible protein 10, macrophage inflammatory protein 2, and tumor necrosis factor alpha, and were expressed in a pattern similar to that induced by FG-Ad vectors encoding AdSEAP. Like AdSEAP, and consistent with the pattern of cellular gene expression, HD-AdLacZ and HD-AdSEAP induced the recruitment of CD11b-positive leukocytes to the transduced liver within hours of administration. AdSEAP also induced a second phase of liver inflammation, consisting of inflammatory gene expression and CD3-positive lymphocytic infiltrates 7 days posttransduction. In contrast, beyond 24 h no infiltrates or expression of inflammatory genes was detected in the livers of mice receiving HD-AdSEAP. Despite the lack of liver inflammation at 7 days, Ad-specific cytotoxic T lymphocytes could be detected in mice receiving HD-AdSEAP. This lack of liver inflammation was not due to reduced transduction since levels of transgene expression and the amounts of vector DNA in the liver were equivalent in mice receiving HD-AdSEAP and AdSEAP. These results demonstrate that HD-Ad vectors induce intact innate but attenuated adaptive immune responses in vivo.

Authors+Show Affiliations

Faculty of Medicine, University of Calgary, 3330 Hospital Dr. N.W., Calgary, AB, T2N 4N1 Canada. dmuruve@ucalgary.caNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

15140994

Citation

Muruve, Daniel A., et al. "Helper-dependent Adenovirus Vectors Elicit Intact Innate but Attenuated Adaptive Host Immune Responses in Vivo." Journal of Virology, vol. 78, no. 11, 2004, pp. 5966-72.
Muruve DA, Cotter MJ, Zaiss AK, et al. Helper-dependent adenovirus vectors elicit intact innate but attenuated adaptive host immune responses in vivo. J Virol. 2004;78(11):5966-72.
Muruve, D. A., Cotter, M. J., Zaiss, A. K., White, L. R., Liu, Q., Chan, T., Clark, S. A., Ross, P. J., Meulenbroek, R. A., Maelandsmo, G. M., & Parks, R. J. (2004). Helper-dependent adenovirus vectors elicit intact innate but attenuated adaptive host immune responses in vivo. Journal of Virology, 78(11), 5966-72.
Muruve DA, et al. Helper-dependent Adenovirus Vectors Elicit Intact Innate but Attenuated Adaptive Host Immune Responses in Vivo. J Virol. 2004;78(11):5966-72. PubMed PMID: 15140994.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Helper-dependent adenovirus vectors elicit intact innate but attenuated adaptive host immune responses in vivo. AU - Muruve,Daniel A, AU - Cotter,Matthew J, AU - Zaiss,Anne K, AU - White,Lindsay R, AU - Liu,Qiang, AU - Chan,Trevor, AU - Clark,Sharon A, AU - Ross,P Joel, AU - Meulenbroek,Robert A, AU - Maelandsmo,Gunhild M, AU - Parks,Robin J, PY - 2004/5/14/pubmed PY - 2004/6/21/medline PY - 2004/5/14/entrez SP - 5966 EP - 72 JF - Journal of virology JO - J Virol VL - 78 IS - 11 N2 - Helper-dependent adenovirus (HD-Ad) vectors with all adenoviral genes deleted mediate very long-term expression of therapeutic transgenes in a variety of animal models of disease. These vectors are associated with reduced toxicity and improved safety relative to traditional early region 1 deletion first-generation Ad (FG-Ad) vectors. Many studies have clearly demonstrated that FG-Ad vectors induce innate and adaptive immune responses in vivo; however, a comprehensive analysis of host immune responses to HD-Ad vectors has not yet been performed. In DBA/2 mice, intravenous injection of HD-Ad vectors encoding LacZ (HD-AdLacZ) or a murine secreted alkaline phosphatase (HD-AdSEAP) induced an early expression of inflammatory cytokine and chemokine genes in the liver, including interferon-inducible protein 10, macrophage inflammatory protein 2, and tumor necrosis factor alpha, and were expressed in a pattern similar to that induced by FG-Ad vectors encoding AdSEAP. Like AdSEAP, and consistent with the pattern of cellular gene expression, HD-AdLacZ and HD-AdSEAP induced the recruitment of CD11b-positive leukocytes to the transduced liver within hours of administration. AdSEAP also induced a second phase of liver inflammation, consisting of inflammatory gene expression and CD3-positive lymphocytic infiltrates 7 days posttransduction. In contrast, beyond 24 h no infiltrates or expression of inflammatory genes was detected in the livers of mice receiving HD-AdSEAP. Despite the lack of liver inflammation at 7 days, Ad-specific cytotoxic T lymphocytes could be detected in mice receiving HD-AdSEAP. This lack of liver inflammation was not due to reduced transduction since levels of transgene expression and the amounts of vector DNA in the liver were equivalent in mice receiving HD-AdSEAP and AdSEAP. These results demonstrate that HD-Ad vectors induce intact innate but attenuated adaptive immune responses in vivo. SN - 0022-538X UR - https://www.unboundmedicine.com/medline/citation/15140994/Helper_dependent_adenovirus_vectors_elicit_intact_innate_but_attenuated_adaptive_host_immune_responses_in_vivo_ L2 - https://journals.asm.org/doi/10.1128/JVI.78.11.5966-5972.2004?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -