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To review the current literature regarding immunostimulatory sequences of DNA for immunotherapy with respect to signaling mechanisms, cytokine profiles, structural characteristics and the applicability and success of this strategy to treat allergic disease.The binding of synthetic DNA-based immunotherapy agents composed of unmethylated cytosine–guanine dinucleotides (CpG ODN) to toll-like receptors have been found to be species-specific. CpG ODNs are capable of inducing a shift in the cytokine profile and immune response that favors the Th1 pathway and suppresses the Th2 pathway. This makes using CpG ODNs a promising candidate for the treatment of allergic diseases, which are known to be mediated by Th2-based response. Current CpG ODN studies have demonstrated prevention and reversal of acute allergen inflammation, airway hyper-reactivity and remodeling. Early animal and human trials of CpG ODNs have shown them to be both well tolerated and effective.The use of immunostimulatory sequences in immunotherapy, although still in the early stages of development, has thus far been shown to be both well tolerated and effective, and offers the potential for a better tolerated, more rapid, more efficacious and longer-lasting therapy over current immunotherapy protocols.