title: Enhancing DNA vaccine potency by coadministration of DNA encoding antiapoptotic proteins.
abstract: Intradermal vaccination by gene gun efficiently delivers DNA vaccines into DCs of the skin, resulting in the activation and priming of antigen-specific T cells in vivo. DCs, however, have a limited life span, hindering their long-term ability to prime antigen-specific T cells. We reason that a strategy that prolongs the survival of DNA-transduced DCs will enhance priming of antigen-specific T cells and DNA vaccine potency. Here we show that codelivery of DNA encoding inhibitors of apoptosis (BCL-xL, BCL-2, XIAP, dominant negative caspase-9, or dominant negative caspase-8) with DNA encoding model antigens prolongs the survival of transduced DCs. More importantly, vaccinated mice exhibited significant enhancement in antigen-specific CD8+ T cell immune responses, resulting in a potent antitumor effect against antigen-expressing tumors. Among these antiapoptotic factors, BCL-xL demonstrated the greatest enhancement in antigen-specific immune responses and antitumor effects. Thus, coadministration of DNA vaccines with DNA encoding antiapoptotic proteins represents an innovative approach to enhance DNA vaccine potency.
authors.affiliation: Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.forename: Morris
authors.initials: M
authors.lastname: Ling
authors.forename: Jeremy
authors.initials: J
authors.lastname: Juang
authors.forename: Liangmei
authors.initials: L
authors.lastname: He
authors.forename: J Marie
authors.initials: JM
authors.lastname: Hardwick
authors.forename: Sharad
authors.initials: S
authors.lastname: Kumar
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics; D017209:Apoptosis; D019470:Biolistics; D039521:CD11c Antigen / Q000032:analysis; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D053148:Caspase 3; D020169:Caspases / Q000235:genetics; D004247:DNA / Q000008:administration & dosage*; D003713:Dendritic Cells / Q000502:physiology; D005260:Female; D051907:Lysosomal Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D009856:Oncogene Proteins, Viral / Q000276:immunology; D050725:Papillomavirus E7 Proteins; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*; D051020:bcl-X Protein
chemical_list: D015703:Antigens, CD; C494812:Bcl2l1 protein, mouse; D039521:CD11c Antigen; D051907:Lysosomal Membrane Proteins; D009856:Oncogene Proteins, Viral; D050725:Papillomavirus E7 Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D019444:Vaccines, DNA; D051020:bcl-X Protein; C059731:oncogene protein E7, Human papillomavirus type 16; D004247:DNA; C505407:CASP3 protein, human; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases