The long-term goals of this project are to develop novel immune response-modifying vaccines for the treatment of asthma. Asthma is a major public health problem, and affects 15 million Americans, roughly 5-8 percent of the population. It has increased substantially in prevalence and in terms of mortality and morbidity over the past two decades, and this increase has occurred despite a substantial improvement in our understanding of asthma pathophysiology and the availability of improved medications for asthma. We propose to generate therapeutic fusion proteins and constructs for asthma by molecularly linking a prototypic allergen, ovalbumin (OVA), to an immune response polarizing cytokine, IL-18, and to a tolerogenic agent, cholera toxin, subunit B. We will use these immunotherapeutic agents in a murine model for asthma, and convert established, pathogenic Th2-dominated, allergic inflammatory responses into protective responses. The proposed studies are based on our previous results, which demonstrated that allergen immunotherapy improves allergic disease by correcting the underlying immune dysregulation, and that the efficacy of immunotherapy can be greatly improved by the use of antigen-cytokine fusion constructs. These constructs, by directing the activity of potent cytokines and other agents towards antigen-specific T cells, rectify the cytokine profile and activity of such pathogenic allergen-specific Th2 cells. Here we propose to produce and study more potent allergen-fusion proteins as well as cDNA plasmid vaccines containing OVA and IL-18 in established models of allergic inflammation and airway hyperreactivity. In addition, we will determine the role of allergen specific Th1 cells, other regulatory T cells (Th3, CD8, or gammadelta T cells), and of peripheral tolerance in down regulating allergic inflammation and asthma. These innovative studies will provide the basis for development of new disease-modifying strategies to treat and potentially cure patients with allergy and asthma. In addition, these studies will expand our understanding of the role of T cells that protect against these common disorders.
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