title: Encapsulating immunostimulatory CpG oligonucleotides in listeriolysin O-liposomes promotes a Th1-type response and CTL activity.
abstract: Immunostimulatory sequences (ISS) are short DNA sequences containing unmethylated CpG dimers that have multiple effects on the host immune system, including the ability to stimulate antigen-specific cytotoxic T lymphocytes (CTLs) and drive Th1-type immune responses. Listeriolysin O (LLO)-containing pH-sensitive liposomes have been shown to efficiently deliver macromolecules to the cytosol of APCs and efficiently stimulate CTLs. We hypothesized that encapsulating ISS-oligodeoxyribonucleotides (ODNs) in this delivery system would enhance the cell-mediated immune response and skew Th1-type responses in protein antigen-based vaccination utilizing LLO-liposomes. In vitro studies indicated that coencapsulation of ISS in LLO-liposomes engendered activation of the NF-κB pathway while maintaining the efficient cytosolic delivery of antigen mediated by the coencapsulated LLO. Antigen-specific CTL responses monitored by using the model antigen ovalbumin (OVA) in mice were enhanced when mice were immunized with OVA and ISS-ODN-containing LLO-liposomes compared with those immunized with OVA-containing LLO-liposomes. The enhanced immune responses were of the Th1-type as monitored by the robust OVA-specific IgG2a induction and the OVA CD8 peptide-stimulated IFN-γ secretion. Our study suggests that including ISS-ODN in LLO-containing pH-sensitive liposomes yields a vaccine delivery system that enhances the cell-mediated immune response and skews this response toward the Th1-type.
authors.affiliation: Department of Pharmaceutical Sciences, University of Michigan, Ann Arbor, Michigan 48109, United States.
authors.forename: Chasity D
authors.initials: CD
authors.lastname: Andrews
authors.forename: Myung-Sook
authors.initials: MS
authors.lastname: Huh
authors.forename: Kathryn
authors.initials: K
authors.lastname: Patton
authors.forename: Debbie
authors.initials: D
authors.lastname: Higgins
authors.forename: Gary
authors.initials: G
authors.lastname: Van Nest
authors.forename: Gary
authors.initials: G
authors.lastname: Ott
authors.forename: Kyung-Dall
authors.initials: KD
authors.lastname: Lee
mesh_terms: D000276:Adjuvants, Immunologic / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001427:Bacterial Toxins / Q000737:chemistry*; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006360:Heat-Shock Proteins / Q000737:chemistry*; D006460:Hemolysin Proteins / Q000737:chemistry*; D007371:Interferon-gamma; D018664:Interleukin-12 / Q000378:metabolism; D008081:Liposomes / Q000737:chemistry*; D051379:Mice; D008810:Mice, Inbred C57BL; D009838:Oligodeoxyribonucleotides / Q000737:chemistry* / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000276:Adjuvants, Immunologic; D001427:Bacterial Toxins; C408982:CPG-oligonucleotide; D006360:Heat-Shock Proteins; D006460:Hemolysin Proteins; D008081:Liposomes; D009838:Oligodeoxyribonucleotides; D018664:Interleukin-12; D007371:Interferon-gamma; C038705:hlyA protein, Listeria monocytogenes