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Antigenic determinants of asthma-associated allergens for design of immunotherapy.

用于免疫治疗设计的哮喘相关过敏原的抗原决定因素。

基本信息

批准号：
9540201
负责人：
MARTIN D. CHAPMAN
金额：
$ 10.03万
依托单位：
INDOOR BIOTECHNOLOGIES
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-25 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9540201
关键词：
Accident and Emergency department Admission activity Affect Allergens Allergic Allergic Disease Allergic Reaction Amino Acids Antibodies Antibody Formation Antibody Repertoire Antibody Response Asthma Award B-Lymphocyte Epitopes B-Lymphocytes Binding Biological Assay Blood Caspase Cells Characteristics Child Clinical Research Complex Crystallization Data Data Set Databases Dermatophagoides farinae antigen f 1 Dermatophagoides pteronyssinus Dermatophagoides pteronyssinus antigen p 1 Dermatophagoides pteronyssinus antigen p 2 Development Engineering Enzyme-Linked Immunosorbent Assay Epitopes Escherichia coli Funding Goals Grant Health Homologous Gene Human Hypersensitivity IgE Immune Immune response Immunoglobulin G Immunologics Immunotherapeutic agent Immunotherapy Innate Immune System Libraries Lung Inflammation Mediator of activation protein Mites Molecular Molecular Conformation Mus Patients Phage Display Phase Pichia Prevalence Production Property Pyroglyphidae Recombinants Reporting Risk Factors Site-Directed Mutagenesis Specificity Structure T-Cell Activation T-Cell Proliferation T-Lymphocyte Technology Testing Time Toll-like receptors Vaccine Design Vaccines Variant X-Ray Crystallography asthmatic asthmatic patient cockroach allergen combinatorial cytokine design immunoreactivity impaired capacity improved indoor allergen innovation lipopolysaccharide-binding protein mutant public health relevance pyroglyphid response screening three dimensional structure tool

项目摘要

DESCRIPTION (provided by applicant): Allergic reactions to house dust mite are an important health problem worldwide, affecting up to 85% of asthmatic children, and are a risk factor for emergency room admission with asthma. Group 1 and 2 mite allergens account for more than 50% of total house dust mite specific IgE reactivity in mite allergic patients. Mite allergens Der p 1 and Der f 1 are cysteine proteases produced by the dust mites Dermatophagoides pteronyssinus and D. farinae, respectively. Proteolytic activity of Der p 1 may enhance IgE antibody production and contribute to lung inflammation in asthma. In contrast, group 2 mite allergens are lipopolysaccharide binding proteins. Der p 2 has been reported to mimic a human structural-homolog that activates the innate immune system through toll like receptors. Despite these important molecular differences between proteolytic group 1 and non-proteolytic group 2, a high IgE prevalence of 83% to allergens from both groups has been observed in mite allergic patients in the US. The main goal of this project is to investigate the antigenic structure of both groups of mite allergens, for the design of immunotherapy. Allergens will be co-crystallized with IgE antibody constructs selected by phage display technology. The key amino acids involved in IgE antibody binding will be identified and modified. The specific aims are: 1) selection of IgE antibody constructs (scFv) from combinatorial libraries made from blood of mite allergic patients using phage display technology; 2) mapping of antigenic determinants on groups 1 and 2 dust mite allergens by X-ray crystallography and analysis of IgE antibody binding epitopes; and 3) site-directed mutagenesis of IgE antibody epitopes for expression of hypoallergenic mutants with T cell reactivity as candidates for immunotherapy. An analysis of the association between mite allergen-specific IgE antibodies from the human repertoire and the epitopes recognized by these IgE antibodies will be performed with the information obtained in the first two aims. Aim #2 will generate experimental data sets of three-dimensional structures of B-cell epitopes that are missing in current databases used for developing tools for B cell epitope prediction. Most importantly, this project will define IgE antibody responses to mite allergens and will provide the structural basis for rational design of hypoallergens. In Aim #3, IgE antibody binding to the epitope mutants will be analyzed by ELISA, multiplex array technology and cell mediator release assays, and T cell reactivity will be evaluated. Mutants will be compared and hypoallergenic forms will be selected for the design of vaccines for immunotherapy of mite allergy.