title: Soluble cytokines can act as effective adjuvants in plasmid DNA vaccines targeting self tumor antigens.
abstract: There are few vaccination strategies available for the reproducible generation of a cytotoxic T cell (CTL) response, particularly in the setting of immunizing against a tumor antigen. Plasmid-based DNA vaccination offers several advantages as compared to MHC class I peptide-based vaccines or DNA immunization using viral vectors. Plasmid-based DNA vaccines are easily produced, can potentially elicit both an MHC class I and class II response, and have little infectious potential. Plasmid-based vaccines, however, have been poorly immunogenic. The systemic immune response generated after plasmid vaccination relies on in vivo transfection of local antigen presenting cells (APC) and both direct presentation and "cross priming" of antigen by professional and non-professional APC. Therefore, methods to enhance the function of APC, such as simultaneous inoculation with plasmids encoding cytokine genes, has resulted in an enhancement of detectable immunity after vaccination. We questioned whether local application of soluble cytokines would be effective in enhancing the systemic immune response elicited after DNA vaccination. Using a self-tumor antigen model, we vaccinated rats with a plasmid-based rat neu intracellular domain (ICD) DNA construct and either no adjuvant, soluble GM-CSF, or IL-12. We demonstrate that the addition of soluble GM-CSF or IL-12 to rat neu ICD DNA vaccination elicits detectable neu specific T cell immunity; specifically the generation of CTL. Antibodies directed against rat neu were not elicited with this approach, indicating that the neu specific T cell immune response elicited with plasmid DNA was skewed towards cell-mediated rather than humoral immunity.
authors.affiliation: Division of Oncology, University of Washington, Seattle, Washington 98195-6527, USA. ndisis@u.washington.edu
authors.forename: Mary L
authors.initials: ML
authors.lastname: Disis
authors.forename: Faith M
authors.initials: FM
authors.lastname: Shiota
authors.forename: Douglas G
authors.initials: DG
authors.lastname: McNeel
authors.forename: Keith L
authors.initials: KL
authors.lastname: Knutson
mesh_terms: D000276:Adjuvants, Immunologic; D000818:Animals; D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D000941:Antigens / Q000737:chemistry; D000951:Antigens, Neoplasm / Q000737:chemistry*; D001324:Autoantigens; D002455:Cell Division; D016207:Cytokines / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism; D018664:Interleukin-12 / Q000378:metabolism; D009369:Neoplasms / Q000517:prevention & control* / Q000628:therapy; D010957:Plasmids / Q000378:metabolism*; D051381:Rats; D011916:Rats, Inbred F344; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D019444:Vaccines, DNA
chemical_list: D000276:Adjuvants, Immunologic; D000941:Antigens; D000951:Antigens, Neoplasm; D001324:Autoantigens; D016207:Cytokines; D019444:Vaccines, DNA; D018664:Interleukin-12; D016178:Granulocyte-Macrophage Colony-Stimulating Factor