The long term goals of this project are to determine and understand the role of CD4 Th cell subsets in the development, maintenance, reduction, and prevention of allergen-induced airway hyperreactivity. We and others have shown that Th2 cells play a major role in producing and exacerbating allergic inflammation, and it has been assumed that Th cells with the """"""""alternative"""""""" cytokine profile (i.e., Th1 cells) inhibit and prevent allergic inflammation in nonallergic individuals. Preliminary data in our laboratory however, indicate that antigen-specific Th1 cell lines when transferred into recipient mice, do not down regulate airway hyperreactivity but instead cause severe lung disease. This suggests that cell types other than Th1 cells (e.g., those producing TGF-beta), and other cellular processes may be involved in protective immune responses to allergens that down regulate and prevent allergic inflammatory responses in normal nonallergic individuals. The goals therefore of this proposal are to directly examine the capacity of Th1 cells and other types of regulatory cells to mitigate allergic inflammation and allergen- induced airway hyperreactivity. We will directly examine: 1. the role of Th1 and ThO cells in allergic airway hyperreactivity (a model for asthma). 2. the role of TGF-beta producing cells (established by gene transfer) in the regulation of airway hyperreactivity. 3. specific mechanisms that induce tolerance and inhibit airway hyperreactivity in mice rendered unresponsive to ovalbumin (e.g., the role of antigen presentation by B cells and by alveolar macrophages, and the role of costimulation with CTLA-4). We have established several unique models for airway hyperreactivity and intranasal tolerance, have assembled a broad range of reagents, and have exciting preliminary data to perform the proposed experiments. These innovative studies will expand our understanding of the complexity and diversity of Th cells and of immune responses that protect against allergy and asthma. They will provide the basis for development of new disease-modifying strategies to treat and potentially cure patients with allergy and asthma.
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