Immunostimulatory CpG oligonucleotides: Effect on gene expression and utility as vaccine adjuvants

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.