This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.(from CRISP website)It has been proposed that an inability to control immunoinflammatory processes may be a critical factor in the pathogenesis of asthma. Specific subsets of CD4+ 'T regulatory' (TR) cells promote tolerance to allergens and inhibit airway responsiveness in animal models, and may exert these effects in part through the production of anti-inflammatory cytokines (IL-10, TGF-Beta). Although information in humans is scarce, TR cells appear to be present at the time of birth, but are functionally immature. Information derived from mouse models suggests that stimulation of cytokines such as IL-10 in early life may drive the production of functional TR cells. Considering that exposure to endotoxin, a potent stimulus for IL-10, in childhood is associated with reduced risk for atopic diseases and asthma, this suggests that the risk of developing allergic diseases and/or asthma in early childhood is determined by two interactive factors: first, the degree to which TR cell maturation is developed in early life; and second, the timing, nature, and quantity of environmental exposure to innate immune stimuli. To test this hypothesis, we propose to study an established and well-characterized birth cohort at increased risk for allergies and asthma on the basis of parental history. Retrospective (from stored specimens), cross-sectional, and prospective measurements of immune development will evaluate phenotypic and functional indicators of TR cells during infancy and early childhood in children with a variety of allergic cutaneous and respiratory tract disorders, including asthma. In addition, dust specimens will be collected from the home for quantitative measurement of LPS, peptidoglycan, and selected allergens. Finally, we will analyze the contributions of environmental factors (innate stimuli and allergen exposure) and immunologic development (TR cells and cytokine responses) to the development, resolution, severity, and/or perpetuation of wheezing and/or allergic phenotypes in infancy and early childhood. The proposed experiments will not only measure the development of TR cells and their relationship to wheezing phenotypes and/or childhood asthma, but will also help to define how stimulation of the innate immune system relates to maturation of TR cells.
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