CpG oligodeoxynucleotides: a novel therapeutic approach for atopic disorders

Atopic disorders such as allergic rhinitis, asthma and atopic dermatitis are associated with skewing of immune responses towards a TH2 phenotype, resulting in eosinophilic inflammation. TH2 cytokines promote eosinophil growth, migration and activation, mast cell differentiation, and IgE production, and are candidate mediators of pathologic abnormalities in asthma and other atopic diseases. There has been a significant increase in the prevalence of allergic disorders over the past several decades. Recent epidemiological studies suggest that reduced early-life exposure to strong TH1 stimuli in industrialized counties has skewed the TH1/TH2 balance towards TH2 responses. Improved hygiene, vaccination, and use of antibiotics may contribute to this imbalance. In the last half of the twentieth century we have seen the use of multiple agents to treat atopic disorders, ranging from antihistamines, steroids and leukotriene modifiers to anti-IgE antibodies. All these agents can block symptoms but do not significantly modify the course of the disease. Recent attempts to restore TH1/TH2 balance by blocking TH2 cytokines or inducing TH1 cytokines, have not only failed to alter the outcome of atopic diseases but, in some cases, have caused significant adverse effects. An alternate method of suppressing TH2 responses takes advantage of the innate immune response to bacterial DNA. Oligodeoxynucleotides (ODN) containing sequence motifs centered on unmethylated CG dinucleotides (CpG ODN) resemble bacterial DNA, and like bacterial DNA are immunostimulatory; we and others have shown that CpG ODN can suppress TH2-mediated atopic inflammation without requiring the induction of TH1-type cytokines. These agents may represent a novel therapeutic approach toward restoring immune tolerance in atopic individuals.