| The prevalence of asthma and other allergic diseases is reaching epidemic proportions underscoring the need for the development of novel therapies. Numerous experimental and clinical studies support the concept that CD4+ Th2 cells are responsible for the pathophysiological manifestations of this disease. Thus, it has been hypothesized that agents that selectively induce counterbalancing Th1 immune responses may be useful in inhibiting Th2-mediated responses in asthmatics.; Bacterial DNA has been shown to induce strong Th1-polarized responses both in vitro and in vivo. Recent studies suggest that these agents may be beneficial in downregulating pathogenic Th2 immune responses in asthma. However, many questions regarding the ability of these sequences to reverse established allergic disease still remain. To address these issues, the goals of this thesis were: (1) to determine whether treatment with an allergen-specific DNA sequence (ISS) can prevent or reverse allergic responses in a murine model of ragweed-induced allergic asthma; (2) to establish the safest and most effective dose and route of ISS administration; and (3) to determine the mechanisms by which ISS inhibits these responses in mice. Our studies show that ISS prevents as well as reverses ragweed-induced allergic responses. These inhibitory effects were associated with elevation of Th1 cytokines and Th1-directed IgG2a antibodies and independent of downregulation of Th2 cytokines. Interestingly, comparison of different routes of ISS administration revealed that intradermal delivery was more effective than pulmonary delivery. Furthermore, we demonstrated that the mechanisms by which ISS reverses established asthma are not dependent on allergen-specific antibodies, IL-12 or IFNγ. To explore other potential mechanisms of ISS-induced inhibition of allergic responses, we examined pulmonary gene expression by microarray technology. We identified several candidates such as IL-4 soluble receptor, IgE binding proteins, glucocorticoid receptor and others that might be involved in the protective effects of allergen-specific ISS in the context of ragweed-induced asthmatic responses.; In summary, our studies suggest although more research is needed to dissect the exact mechanisms by which allergen-specific ISS conjugates inhibit allergic responses, these agents are a promising therapy that may provide a safe and effective means of treating the symptoms of asthma in humans. |
