title: Distinct roles of adenovirus vector-transduced dendritic cells, myoblasts, and endothelial cells in mediating an immune response against a transgene product.
abstract: Adenovirus-mediated gene delivery via the intramuscular route efficiently promotes an immune response against the transgene product. In this study, a recombinant adenovirus vector encoding beta-galactosidase (Ad beta Gal) was used to transduce dendritic cells (DC), which are antigen-presenting cells, as well as myoblasts and endothelial cells (EC), neither of which present antigens. C57BL/6 mice received a single intramuscular injection of Ad beta Gal-transduced DC, EC, or myoblasts and were then monitored for anti-beta-galactosidase (anti-beta-Gal) antibody production, induction of gamma interferon-secreting CD8(+) T cells, and protection against melanoma tumor cells expressing beta-Gal. While all transduced cell types were able to elicit an antibody response against the transgene product, the specific isotypes were distinct, with exclusive production of immunoglobulin G2a (IgG2a) antibodies following injection of transduced DC and EC versus equivalent IgG1 and IgG2a responses in mice inoculated with transduced myoblasts. Transduced DC induced a strong ex vivo CD8(+) T-cell response at a level of 50% of the specific response obtained with the Ad beta Gal control. In contrast, this response was 6- to 10-fold-lower in animals injected with transduced myoblasts and EC. Accordingly, only animals injected with transduced DC were protected against a beta-Gal tumor challenge. Thus, in order to induce a strong and protective immune response to an adenovirus-encoded transgene product, it is necessary to transduce cells of dendritic lineage. Importantly, it will be advantageous to block the transduction of DC for adenovirus-based gene therapy strategies.
authors.affiliation: UMR INRA 955, Génétique Moléculaire et Cellulaire, Génétique Virale, Ecole Nationale Vétérinaire d'Alfort, 94704 Maisons-Alfort Cédex, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Mercier
authors.forename: Hanne
authors.initials: H
authors.lastname: Gahéry-Segard
authors.forename: Martine
authors.initials: M
authors.lastname: Monteil
authors.forename: Renée
authors.initials: R
authors.lastname: Lengagne
authors.forename: Jean-Gérard
authors.initials: JG
authors.lastname: Guillet
authors.forename: Marc
authors.initials: M
authors.lastname: Eloit
authors.forename: Caroline
authors.initials: C
authors.lastname: Denesvre
mesh_terms: D000258:Adenovirus Infections, Human / Q000276:immunology; D000260:Adenoviruses, Human / Q000235:genetics*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002460:Cell Line; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation; D004727:Endothelium / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D005260:Female; D005822:Genetic Vectors; D006801:Humans; D007114:Immunization; D008546:Melanoma, Experimental / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018482:Muscle, Skeletal / Q000166:cytology / Q000276:immunology / Q000637:transplantation; D012878:Skin Neoplasms / Q000517:prevention & control; D014161:Transduction, Genetic; D019076:Transgenes; D001616:beta-Galactosidase / Q000235:genetics / Q000378:metabolism
chemical_list: D001616:beta-Galactosidase