These studies are designed to investigate the pathophysiology of the inflammatory response to intrabronchial allergen challenge in asthmatic subjects. These inflammatory responses are expressed clinically as the late asthmatic response (LAR). Initially we will investigate the hypothesis that the LAR develops as a result of quantitative or qualitative differences in mediators released at the time of the immediate response to allergen challenge. In parallel, we will investigate the alternative hypotheses that inflammatory cells from late responders have either a hyperreactive response to pro-inflammatory mediators or that they fail to down- regulate properly in response to inhibitory stimuli. A third possibility is that it is the ability of alveolar macrophages to be triggered to secrete mediators in response to allergen which results in the selective development of a LAR. We will investigate the ability of macrophages to secrete IL-1 and TNF in an IgE- dependent fashion. This will allow us to distinguish whether mast cells or macrophaphages are responsible for the LAR, based on our ability to identify the mast cell-specific product histamine as opposed to the macrophage-specific products IL-1 or TNF. Finally, we will perform a controlled trial of immunotherapy in patients with extrinsic asthma. These latter studies are designed to prospectively investigate the pathophysiological basis by which a successful course of immunotherapy abrogates the LAR to challenge with allergen.
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