Viral respiratory infections appear to facilitate the development of allergen-induced asthma and persistent alterations in airway function by poorly understood mechanisms. Allergen-induced asthma in infants and children is characterized by airway hyperreactivity and inflammation. Th2 cytokines, such as interleukins (IL)-4 and IL-5, produced by allergen-specific T cells of the lung and associated lymphoid tissue are critical in inducing these pathologic features. Allergen-specific tolerance may normally inhibit the Th2 response to foreign proteins entering the lung. The mechanisms responsible for tolerance are poorly understood, as is the role of the loss of tolerance in allergen sensitization and asthma. We hypothesize that during the presentation of allergen to T cells by antigen presenting cells (APCs), the expression of co-stimulatory molecules by the APC is a critical factor for allergen sensitization versus the induction of T cell unresponsiveness or tolerance. This project will use a mouse model of influenza A pulmonary infection to determine if this infection enhances subsequent allergen sensitization and interferes with tolerance induction in vivo. The role of viral-induced increases in interactions between the B7 co-stimulatory molecules on the APC and CD28 on the T cell, and the secretion of beta-chemokines by the APC and their binding to specific C-C chemokine receptors (CCRs) on T cells, will be examined. The importance of increased B7/CD28 or beta-chemokine/CCR interactions in provoking allergen sensitization and allergic pulmonary disease, and in inhibiting the induction of tolerance to aeroallergens will be investigated. In parallel with these animal model studies, human alveolar macrophages and T cells will be obtained from the lungs of asthmatics or non-asthmatic adults that either have or have not experienced recent viral respiratory infection. The capacity of alveolar macrophages to express B7 and beta-chemokine molecules, and to induce either T cell activation or antigen-specific unresponsiveness, will be studied for each of the four groups of human subjects. If indicated, blocking studies will determine whether increased B7/CD28 or beta-chemokine/CCR interactions increases T cell activation and/or inhibits antigen-specific unresponsiveness for a particular group. Together, these studies will substantially increase our understanding of the mechanisms by which surface co-stimulatory molecules and beta- chemokines influence viral-induced allergen sensitization versus tolerance induction in asthma. They may also point out means by which manipulation of co-stimulatory interactions could be exploited therapeutically in the treatment or prophylaxis of allergen-induced asthma.
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