For many asthmatic patients, the syndrome or disease has its roots in infancy. From preliminary observations in humans, and from experiments performed in a rodent model of virus-induced airway dysfunction in our laboratory, two factors appear to influence the development of persistent wheezing or the asthmatic phenotype. First, a hereditary component, which is clinically manifested by the development of allergic diseases, and immunologically mediated by the presence of increased levels of IgE antibody and/or a dysregulation in cytokine production [most likely a decreased production of interferon gamma (IFN-gamma)]. Second, an environmental component, which appears biologically related to the development of a significant viral lower respiratory tract illness (most likely respiratory syncytial virus), and temporarily related tot a critical stage in the physiological development of the lower airway. However, the relative contribution of either of these factors, either alone or in combination, has yet to be clearly established during infancy and/or early childhood. To establish and advance our knowledge about these very important relationships, this grant application proposed to conduct experiments designed to answer the following questions: Is IFN-gamma dysregulated in persistent wheezers or asthmatic children? If so, how early in life can these abnormalities be demonstrated? At birth? Following infection? As the child encounters his/her environment for various periods of time? Is IFN-gamma the only cytokine that can be linked with such outcomes, or can other cytokines be involved as well? If IFN-gamma dysregulation can be shown to be casually linked with various outcomes, what is the mechanisms of the defect? How closely do any demonstratable abnormalities in cytokine responses or regulation track with the development of clinically apparent allergic diseases such as atopic dermatitis, allergic rhinitis, and or asthma? To answer these questions, a prospective longitudinal study has not been designed that will evaluate the interaction and time dependencies of relevant immunological, microbiological, and clinical parameters. The results of these studies will provide information that will be a major step forward in our understanding of the relative influence that genetic and environmental risk factors on the development of childhood asthma.
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