The central hypothesis of this program is that abnormalities in immune regulation orchestrated by T cells are present in subjects with asthma and lead to inflammatory responses within airways. In addition, critical targets adversely affected by T cell derived cytokines are glucocorticoid receptors as well as neural elements and smooth muscle within airways. Studies that address these and other hypotheses will be conducted in man and animal models by investigators representing multiple disciplines and employing the techniques of pulmonary physiology and immunology as well as molecular and cellular biology. In clinical studies, the mechanisms responsible for corticosteroid resistant asthma will be defined. As part of this work, the hypothesis that antigens trigger selective expansion of IL-2 and IL-4 secreting Vbeta8+T cells that induce a combination of glucocorticoid receptor ligand and DNA binding defects will be addressed. The hypothesis that patients with nocturnal asthma have an abnormality in feedback mechanisms involving corticotropin releasing hormone that normally decrease the inflammatory process will be studied. The preliminary observation that subjects with nocturnal asthma have decreased T lymphocyte glucocorticoid receptor binding affinity that is exaggerated at night will be examined to determine if subjects with the lowest receptor binding affinity also have the greatest mRNA expression of IL-2 and IL-4 in biopsy specimens. Utilizing models to address hypotheses that cannot be entertained in humans, the role of T lymphocytes and IgE antibody in altering airway function in allergen-driven models in normal and knockout mice will be defined. Studies involving transfer of immune cells and/or infusions of various isotopes of allergen-specific monoclonal antibodies will be used to address their role in altering airway function. In addition, the cellular and biochemical mechanisms responsible for allergen induced increases in cholinergic input into airways (greater release of acetylcholine from nerve endings) as well as the functional loss of the airways' neurally mediated relaxant pathway (nonadrenergic noncholinergic inhibitory [NANCi] system) will be defined. Changes in the cyclic 3',5'-adenosine monophosphate pathway that may be T cell cytokine-induced as a result of allergen sensitization and challenge will be assessed in study of NANCi responses. This program will provide additional insight into mechanisms responsible for airways inflammation and hyperresponsiveness.
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