Toll-Like Receptor 9 Activation with CpG Oligodeoxynucleotides for Asthma Therapy*

Abstract

Prokaryotic DNA has long been recognized as immunostimulatory. In the last decade the role played by CpG motifs (nucleotide sequence motifs centered on a cytosine-guanine dinucleotide) in bacterial and viral DNA has been elucidated. CpG motifs are detected by the innate immune pattern recognition receptor Toll-like receptor (TLR) 9, the ligation of which activates multiple signal cascades in responding cells. A restricted pattern of TLR9 expression to certain dendritic cells and B cells appears to provide relative specificity in responses, especially in comparison to other TLR ligands. TLR9 activation induces a Th1-like pattern of cytokine release which led to interest in the use of synthetic CpG oligodeoxynucleotides (CpG ODN) for the prevention and treatment of Th2-associated atopic disorders such as asthma. Interestingly, Th1 cytokines do not appear to be necessary for a therapeutic response in preclinical models of atopic asthma. Additional potential mechanisms of action include induction of regulatory-type responses (involving interleukin-10 release), and expression of indoleamine 2,3-dioxygenase. CpG ODN have been shown to prevent and reverse antigen-induced eosinophilic airway inflammation in animal models; human trials are ongoing with encouraging early results when used as a ragweed vaccine adjuvant in allergic upper airway disease.