The objective of this proposal is to increase our understanding of the ways in which fungi or other organisms that can colonize patients contribute to diseases of the respiratory tract. The approach has been to study immune responses to two fungi: Aspergillus fumigatus that commonly grows in the respiratory tract, and dermatophytes of the genus Trichophyton that grow on the skin or nails. The important allergens will be purified, characterized, and cloned to derive the amino acid or nucleotide sequence, as has already been done for Tri t I and Asp fl. Three proteins from A. fumigatus have already been identified, a cDNA library has been established and 3 clones expressing Aspergillus allergens are being evaluated. Skin testing with Trichophyton extracts gives rise to immediate or delayed reactions; the plan is to fully purify a protein that gives delayed hypersensitivity (DH) responses. This protein will be characterized by the proliferative T cell response in vitro, by measurement of serum antibodies and by the histology of the skin response in patients with DH to Trichophyton. In addition, it will be compared to the responses to Tri t I in patients with immediate hypersensitivity. These studies provide a unique opportunity to compare immune responses giving rise to DH with immune responses (induced by the same source of foreign antigen), giving rise to immediate hypersensitivity. In order to further investigate the role of fungi, patients who are colonized and have made an immune response to these organisms will be treated in controlled trials with systemic antifungals: FIuconazole for patients with asthma who are infected with Trichophyton; and Itraconazole for patients with cystic fibrosis colonized with A. fumigatus. Overall, these studies are designed to: i) Identify antigen sources that could be causes of """"""""intrinsic"""""""" asthma; ii) Determine the molecular structure of the antigens; iii) Study the immune response to these antigens both T cells and specific antibodies, in order to understand the ways in which they contribute to lung disease, iv) Answer whether it is possible to develop treatments for intrinsic asthma that are based on the specific etiology.
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