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 β-galactosidase (βgal) model Ag system we find that both in vivo gene transfer systems elicit potent and long-lasting anti-βgal-specific CD8+ and CD4+ T cell responses. However, gene gun immunization predominantly promotes the production of anti-βgal antibodies of the γ1 isotype, indicative of a Th2-biased immune response, while intradermal injection of recombinant adenovirus primarily leads to the production of anti-βgal γ(2a) antibodies, indicative of a Th1-biased immune response. Since viral infections are generally associated with the production of large amounts of IFN-α 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-α or IL-12 resulted in increased production of anti-βgal γ(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.
Bibliographical noteFunding Information:
We thank Dr Michael T Lotze for his generous advice and support. This work was supported in part by a fellowship from the Deutsche Forschungs Gemeinschaft to Thomas Tüting, NIH grants CA 57840 and CA 67407 to Walter J Storkus, and NIH grants CA 64623 and CA 72914 to Albert B DeLeo.
- Cell-mediated immunity
- DNA immunization
- Tumor immunotherapy