Immunostimulatory DNA sequences : an overview

The biochemical and genetic properties of DNA have been thoroughly investigated, yet only recently has it been appreciated that DNA carries more information than simply a blueprint for the regulation and construction of proteins. Indeed, the immune systems of vertebrates appear to have evolved the ability to distinguish the foreign DNA of bacteria and certain viruses from the self-DNA of the host, a new twist on the self vs non-self detection system already well-known for foreign proteins. Specifically, the frequency of unmethylated CpG motifs (CpG denotes covalently linked CG dinucleotides, not C∶G base pairs) is extensively suppressed in vertebrates, including mammals (by at least 20-fold [1]), whereas it is found at the usual frequency (1/16) in most bacterial and viral DNA. There have now been several reports (detailed in Subheadings 2. and 4. ) that bacterial DNA or synthetic oligodeoxyribo-nucleotides (ODNs) containing bacterially derived sequences, stimulate the immune systems of mice and humans to first mount innate, and then antigen-specific (when foreign antigen is present), Th(1)-type responses. This adjuvant effect of bacterial immunostimulatory DNA sequences (ISS) appears to be important for the robust Th(1)-type immune response usually seen in genetic vaccination (2). Although the terms CpG motif and ISS are generally used synonymously in this field, CpG motifs are defined structurally, whereas ISS are defined functionally (and therefore include non-CpG sequences that have been found to be stimulatory).