title: Co-delivery of T helper 1-biasing cytokine genes enhances the efficacy of gene gun immunization of mice: studies with the model tumor antigen beta-galactosidase and the BALB/c Meth A p53 tumor-specific antigen.
abstract: DNA-based immunization is currently being investigated as a new method for the induction of cellular and humoral immunity directed against viral disease and cancer. In the present study we characterized and compared the immune responses induced in mice following particle-bombardment of the skin ('gene gun' immunization) with those elicited by intracutaneous injection of a recombinant adenoviral vector. Using the well characterized beta-galactosidase (beta gal) model Ag system we find that both in vivo gene transfer systems elicit potent and long-lasting anti-beta gal-specific CD8+ and CD4+ T cell responses. However, gene gun immunization predominantly promotes the production of anti-beta gal antibodies of the gamma 1 isotype, indicative of a Th2-biased immune response, while intradermal injection of recombinant adenovirus primarily leads to the production of anti-beta gal gamma 2a antibodies, indicative of a Th1-biased immune response. Since viral infections are generally associated with the production of large amounts of IFN-alpha and IL-12, we investigated whether administration of expression plasmids encoding these Th1-associated cytokines along with antigen-encoding cDNA can influence the nature of the immune response resulting from gene gun immunization. We observed that co-delivery of IFN-alpha or IL-12 resulted in increased production of anti-beta gal gamma 2a antibodies. This suggests a shift towards a Th1 phenotype of the resulting immune response, thus mimicking a viral infection. Importantly, gene gun immunization of mice with a naturally occurring tumor antigen, the tumor-specific p53 mutant antigen expressed by the chemically induced BALB/c Meth A sarcoma, required co-delivery of IL-12 for the induction of effective antitumor immunity. These results have important implications for the design of clinically relevant gene gun immunization strategies for tumor immunotherapy.
authors.affiliation: University of Pittsburgh Cancer Institute, PA 15261, USA.
authors.forename: T
authors.initials: T
authors.lastname: Tüting
authors.forename: A
authors.initials: A
authors.lastname: Gambotto
authors.forename: P D
authors.initials: PD
authors.lastname: Robbins
authors.forename: W J
authors.initials: WJ
authors.lastname: Storkus
authors.forename: A B
authors.initials: AB
authors.lastname: DeLeo
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000097:blood; D000951:Antigens, Neoplasm / Q000235:genetics; D019470:Biolistics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000235:genetics*; D005260:Female; D016158:Genes, p53; D007111:Immunity, Cellular; D007371:Interferon-gamma / Q000235:genetics; D018664:Interleukin-12 / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009369:Neoplasms / Q000276:immunology / Q000628:therapy*; D012867:Skin / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage*; D001616:beta-Galactosidase / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D016207:Cytokines; D019444:Vaccines, DNA; D018664:Interleukin-12; D007371:Interferon-gamma; D001616:beta-Galactosidase