Clinical application of CpG-, non-CpG-, and antisense oligodeoxynucleotides as immunomodulators

Cytosine-phosphate-guanosine (CpG) motifs, found mainly in bacterial DNA, have immunostimulatory effects in humans and have offered new perspectives in the treatment of clinical conditions, including viral and bacterial infections, vaccination, allergy and asthma, and in antitumor therapy. Three classes of CpG-oligodeoxynucleotides (ODNs), CpG-A, -B, and -C, with distinct biological properties and which differ in their sequence and nucleotide backbone, have been characterized. Typically, CpG-ODNs bind to TLR9 in the endosomal compartment and initiate a signaling cascade that leads to activation of proinflammatory transcription factors such as NFkappaB. In addition, non-CpG-ODNs have been shown to modulate the immune system and, although these molecules are devoid of CpG motifs, their biological action appears to require a functional TLR9. In this review, advances in the clinical therapy and prevention of infectious diseases using ODNs, as well as the use of antisense ODNs that specifically target genes and control exaggerated immune responses, are discussed. In addition, an update of selected ODNs that have entered clinical trials is provided.