title: Enhancement of plasmid DNA immunogenicity with linear polyethylenimine.
abstract: The utility of plasmid DNA as an immunogen has been limited by its weak immunogenicity. In the present study, we evaluated the ability of a family of linear polyethylenimine (PEI) polymers, complexed to plasmid DNA, to augment DNA expression in vivo and to enhance antigen-specific adaptive immune responses. We showed that four of five structurally different PEIs that we evaluated increased in vivo DNA expression 20- to 400-fold, and enhanced DNA-induced epitope-specific CD8⁺ T-cell responses 10- to 25-fold in BALB/c and C57BL/6J mice respectively, when delivered intravenously. Functional studies of the PEI-DNA-induced CD8⁺ T-cell responses demonstrated that formulation of DNA with PEI was associated with increased numbers of cells secreting type I cytokines. In addition, PEI-DNA complexes improved antigen-specific T(H) 1-helper cell and humoral responses. Most importantly, the PEI-DNA complexes elicited memory cellular responses, capable of rapid expansion and accelerated clearance of a lethal dose of recombinant Listeria monocytogenes. Lastly, we identified physical properties of PEI-DNA complexes that are associated with enhanced DNA-elicited immunogenicity. These findings demonstrate that PEI polymers can play an important role in the development of DNA-based vaccines in the setting of infectious disease prevention and cancer therapy.
authors.affiliation: Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA. evita.grant@gmail.com
authors.forename: Evita V
authors.initials: EV
authors.lastname: Grant
authors.forename: Mini
authors.initials: M
authors.lastname: Thomas
authors.forename: Jennifer
authors.initials: J
authors.lastname: Fortune
authors.forename: Alexander M
authors.initials: AM
authors.lastname: Klibanov
authors.forename: Norman L
authors.initials: NL
authors.lastname: Letvin
mesh_terms: D056704:Adaptive Immunity / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002470:Cell Survival / Q000187:drug effects; D016207:Cytokines / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D005260:Female; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000737:chemistry / Q000648:ultrastructure; D010957:Plasmids / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011094:Polyethyleneimine / Q000737:chemistry / Q000494:pharmacology*; D013047:Specific Pathogen-Free Organisms; D018709:Statistics, Nonparametric; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000737:chemistry / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D019444:Vaccines, DNA; D011094:Polyethyleneimine