title: Enhancing DNA vaccine potency by combining a strategy to prolong dendritic cell life with intracellular targeting strategies.
abstract: We have recently shown that intradermal coadministration of DNA encoding Ag with DNA encoding inhibitors of apoptosis, including Bcl-x(L), prolongs dendritic cell (DC) life and thereby enhances the potency of DNA vaccines in vivo. We have also demonstrated that DNA vaccines targeting Ag to subcellular compartments, using proteins such as Mycobacterium tuberculosis heat shock protein 70, calreticulin, or the sorting signal of the lysosome-associated membrane protein type 1 (LAMP-1), enhanced DNA vaccine potency. In this study, we reasoned that the combination of a strategy to prolong DC life with intracellular targeting strategies might produce a more effective DNA vaccine against human papillomavirus E7. We showed that coadministration of DNA encoding Bcl-x(L) with DNA encoding E7/heat shock protein 70, calreticulin/E7, or Sig/E7/LAMP-1 resulted in further enhancement of the E7-specific CD8(+) T cell response for all three constructs. Of these strategies, mice vaccinated with Sig/E7/LAMP-1 DNA mixed with Bcl-x(L) DNA showed the greatest increase in E7-specific CD8(+) T cells ( approximately 13-fold increase). This combination of strategies resulted in increased CD8(+) T cell functional avidity, an increased E7-specific CD4(+) Th1 cell response, enhanced tumor treatment ability, and stronger long-term tumor protection when compared with mice vaccinated without Bcl-x(L) DNA. Therefore, DNA vaccines that combine strategies to enhance intracellular Ag processing and prolong DC life have potential clinical implications for control of viral infection and neoplasia.
authors.affiliation: Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD 21205, USA.
authors.forename: Tae Woo
authors.initials: TW
authors.lastname: Kim
authors.forename: Chien-Fu
authors.initials: CF
authors.lastname: Hung
authors.forename: David
authors.initials: D
authors.lastname: Boyd
authors.forename: Jeremy
authors.initials: J
authors.lastname: Juang
authors.forename: Liangmei
authors.initials: L
authors.lastname: He
authors.forename: Jeong Won
authors.initials: JW
authors.lastname: Kim
authors.forename: J Marie
authors.initials: JM
authors.lastname: Hardwick
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000235:genetics / Q000494:pharmacology*; D000818:Animals; D015703:Antigens, CD / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D015704:CD4 Antigens / Q000235:genetics; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000821:virology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000821:virology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000235:genetics; D003713:Dendritic Cells / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D004338:Drug Combinations; D016503:Drug Delivery Systems / Q000379:methods*; D018984:Epitopes, T-Lymphocyte / Q000008:administration & dosage / Q000276:immunology; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D007424:Intracellular Fluid / Q000276:immunology* / Q000378:metabolism; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D051907:Lysosomal Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009856:Oncogene Proteins, Viral / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D050725:Papillomavirus E7 Proteins; D010957:Plasmids; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology / Q000821:virology; D019444:Vaccines, DNA / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology*; D051020:bcl-X Protein
chemical_list: D000276:Adjuvants, Immunologic; D015703:Antigens, CD; C494812:Bcl2l1 protein, mouse; D015704:CD4 Antigens; D004338:Drug Combinations; D018984:Epitopes, T-Lymphocyte; 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; D007371:Interferon-gamma