title: Immunostimulatory CpG oligonucleotides: Effect on gene expression and utility as vaccine adjuvants.
abstract: Synthetic oligodeoxynucleotides (ODN) containing unmethylated CpG motifs mimic the immunostimulatory activity of bacterial DNA. CpG ODN directly stimulate B cells and plasmacytoid dendritic cells (pDC), promote the production of Th1 and pro-inflammatory cytokines, and trigger the maturation/activation of professional antigen presenting cells. CpG ODN are finding use as vaccine adjuvants, where they increase the speed, magnitude and duration of vaccine-specific immune responses. For example, CpG ODN significantly prolong the protection induced by AVA (Anthrax Vaccine Adsorbed). Unexpectedly, a majority of animals immunized with CpG-adjuvanted AVA maintain resistance to anthrax infection even after their Ab titers decline to sub-protective levels. This survival is mediated by the de novo production of protective Abs by high affinity long-lived memory B cells. The immunostimulatory activity of CpG ODN was probed at the molecular level by microarray. Results show that a small group of 'inducers' rapidly up-regulated a large network genes following CpG treatment of mice. This stimulatory activity is quenched by 'suppressors' that down-regulate the expression of targeted genes, including most of the 'inducers'. These findings shed light on the mechanism underlying CpG-mediated immune activation and therapeutic activity.
authors.affiliation: Cancer and Inflammation Program, National Cancer Institute, Frederick, MD 21702, United States. klinmand@mail.nih.gov
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Klinman
authors.forename: Sven
authors.initials: S
authors.lastname: Klaschik
authors.forename: Koji
authors.initials: K
authors.lastname: Tomaru
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Shirota
authors.forename: Debra
authors.initials: D
authors.lastname: Tross
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Ikeuchi
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000881:Anthrax / Q000276:immunology / Q000517:prevention & control*; D022122:Anthrax Vaccines / Q000276:immunology*; D000907:Antibodies, Bacterial / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D007156:Immunologic Memory; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D009838:Oligodeoxyribonucleotides / Q000276:immunology*; D020411:Oligonucleotide Array Sequence Analysis; D018417:Th1 Cells / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D022122:Anthrax Vaccines; D000907:Antibodies, Bacterial; C408982:CPG-oligonucleotide; D016207:Cytokines; D009838:Oligodeoxyribonucleotides