IN VITRO APPROACH TO PROBLEMS OF CLINICAL ALLERGY

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The aim of this grant is to translate laboratory findings into improvements in clinical practice. A first area concerns insect hypersensitivity. Venom immunotherapy is highly protective; recent work suggests that it may be curative since it can be stopped after five years. We wish to confirm this, to define the duration of protection, and to understand the mechanism by which this occurs. Another goal is to understand the natural history of insect allergy. We have demonstrated that 4% of the population is insect sensitive by history and that 25% have IgE antibodies against insect venoms. These patients will be studied prospectively to establish the relationship between historical and immunologic parameters and hopefully will allow us to prospectively identify patients at serious risk of sting. Finally, we intend to use purified insect venoms to increase the accuracy of skin test diagnosis. A second area relates to immunotherapy for inhalant allergies. In the context of immunotherapy for asthma, we will relate clinical protection to changes in releasability parameters (i.e. changes in basophil release to a variety of secretagogues) and changes in mediator release and cells in acute and late phase reactions. Immunotherapy for allergic rhinitis leads to a decreased response to nasal antigen challenge in the acute phase; we suspect that decrement of the late phase will be even more dramatic. Both phases of this response will be assessed before and during immunotherapy. Finally, we will ascertain whether immunotherapy for inhalant allergy can be terminated after five years. The third area of study utilizes a novel system of nasal allergen challenge and lavage measuring mediators (histamine, PGD, kinins, TAME esterase, leukotrienes, chemotactic factors) and cells (lymphocytes, cosinophils and neutrophils) and a macrophage-derived histamine releasing factor which is found in late phase reactions and which acts by cross-linking IgE. We will assess various pharmacologic agonists in this system. Both standard and novel agents will be chosen based on their effects in vitro on basophil and mast cell mediator release. We have shown that cold, dry air challenge (a model of exercise-induced asthma) also causes mediator release from clinically sensitive persons and will study pharmacologic agonists in this model. In this instance the in vitro screen involves release by hyperosmolar stimuli, which we postulate is the mechanism of cold air induced release in vivo.