Phylogenetic Approach to Plant Allergy Vaccines

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DESCRIPTION (provided by applicant): Allergic diseases of the airways, including asthma and allergic rhinitis are increasing in industrialized countries, where up to 30% of some populations are now affected. Cedar pollen is a major cause of seasonal allergic rhinitis (pollinosis) in Central U.S.A, Southern Europe and Japan. Effective immunization holds the greatest promise for preventing and treating allergic diseases. Current immunotherapy is limited by the risk of producing IgE-mediated, localized or anaphylactic reactions. The hypothesis to be tested in this proposal is that the molecular biodiversity of plants can be used to identify natural sources of allergens with reduced capacity to bind IgE, while retaining their capacity to induce T-helper cell responses. The specific aims to test this hypothesis are to: 1) Create a library of genetic sequences for homologues of two major mountain cedar allergens, by PCR amplification and automated nucleotide sequencing of genomic and cDNA from up to 138 cedar / cypress species. 2) Identify within this library genetic variants of the allergens, in which the amino acid sequence of the IgE binding sites (epitopes) differ from those of the sensitizing allergens and use novel computational algorithms and automated homology modeling to determine in which variants the 3-D structures of one or more IgE epitopes are likely to be disrupted. 3) Express the genes for the selected variants of the allergens as fusion proteins and test their binding of serum IgE from cedar allergic patients from Central U.S.A, Southern Europe and Japan, their ability to induce degranulation of blood basophils from cedar-allergic patients, and to induce T-helper responses. These studies will be performed by an established, multidisciplinary team of immunologists, structural biologists and a botanist, who have experience in the discovery and characterization of cedar allergens. Successful completing these studies will result in a new generation of allergy vaccines, the efficacy of which can be tested, without expensive safety testing. A better understanding of the structural characteristics of allergenic epitopes will expedite the development of new vaccines against numerous allergens.