MOLECULAR STUDIES OF ANTIGENS THAT CAUSE LUNG DISEASE

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On a worldwide basis, allergic sensitization to allergens produced by house dust mites is the most important risk factor for the development of asthma. Over 10 different mite allergens have been identified by gene cloning techniques. The aims of this proposal are to determine the molecular structure of the Group 2 allergens and to develop allergen variants that have reduced reactivity with IgE antibodies. The tertiary structure of Der p 2 will be determined by nuclear magnetic resonance spectroscopy (NMR) and by X-ray crystallography. Der p 2 variants will be generated by site directed mutagenesis and the reactivity of these variants will be assessed by immediate skin tests, serum IgE antibody responses and T cell responses. Variants which show reduced skin test reactivity, but retain T cell epitopes, will be selected for use in a Phase I study of immunotherapy in mite allergic patients. IgE antibody and T cell responses to Dermatophagoides Group 1, 2, 5, and 7 allergens will be compared to determine their relative allergenic importance and to select cocktails of recombinant allergens for diagnostic and therapeutic purposes. Allergens produced by a second mite species, Blomia tropicalis, which is an important cause of asthma in the tropics, will be cloned and their allergenic relationships will be investigated. These studies will initially focus on the Group 5 allergens and a multi-center skin test study will be carried out at several international centers to compare the biologic activity of Blo t 5 and Der p 5. This will enable the suitability of recombinant allergens for diagnosis to be evaluated and sensitization to Blomia and Dermatophagoides spp. to be compared in different geographic areas. The expected outcome of these studies is that the structure and biologic significance of the most important mite allergens will be determined, and that recombinant proteins will be produced for allergy diagnosis and treatment, which have fewer side effects that natural allergen extracts, for use in developing better immunotherapies for asthma.