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Mechanisms of Allergen-induced Type 2 Immunity

过敏原诱导的 2 型免疫机制

基本信息

批准号：
10182141
负责人：
Hirohito Kita
金额：
$ 40.92万
依托单位：
MAYO CLINIC ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-11-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10182141
关键词：
Address Allergens Allergic Allergic Disease Alternaria Ambrosia Antibodies Antibody Formation Antigens Asthma Biological CD4 Positive T Lymphocytes Cell physiology Cells Collaborations Data Development Disease Environmental Risk Factor Eosinophilia Epithelial Epithelium Exposure to Food Hypersensitivity Functional disorder Funding Genes Genomic approach Grant Hay fever Helper-Inducer T-Lymphocyte Heterogeneity Human IgE Immune Immune response Immunity Immunologics Inhalation Interleukin-13 Interleukin-4 Interleukin-5 Interleukins Mediating Mucous Membrane Mus Outcome Pathology Pathway interactions Patients Phenotype Play Production Prospective Studies Recombinant Proteins Regulation Role Serum Structure of germinal center of lymph node T-Lymphocyte TSLP gene Testing airborne allergen airway inflammation arm base beta-Galactosidase cell type clinical phenotype cytokine disease phenotype draining lymph node eosinophilic inflammation functional genomics fungus genetic approach microbial mouse genetics mouse model novel novel therapeutics peripheral blood prevent respiratory health response

项目摘要

PROJECT SUMMARY/ABSTRACT The long-term objective of this grant is to investigate how airway exposure to natural allergens leads to development of type 2 immunity and allergic diseases. Exaggerated type 2 immune responses are implicated in a wide variety of disorders ranging from asthma to food allergy. Traditionally, CD4+ type 2 helper T (Th2) cells that produce interleukin (IL)-4, IL-5, and IL-13 have been considered major players in directing the pathophysiology of these diseases, such as airway eosinophilia and IgE antibody production. However, it remains unresolved whether Th2 cells alone can explain the spectrum of clinical phenotypes of disease. For example, not all patients with asthma develop IgE antibodies to allergens, and not all patients with detectable serum IgE antibody levels develop asthma. T follicular helper (Tfh) cells are a newly defined subset of CD4+ T cells that are distinguished from other T cells by their selective role in orchestrating germinal center responses. Our observations during the last funding period demonstrate a pivotal role for IL-4-producing Tfh cells in the regulation of IgE antibody production, but not in airway inflammation, suggesting that adaptive “type 2 immunity” may in fact consist of at least two pathways. In the next funding period, we will extend these studies and define how allergen exposure mediates various immunologic and clinical phenotypes of allergic diseases. In Aim 1, we will examine the roles of Tfh cells and Th2 cells in allergic immune responses induced by exposure to natural airborne allergens. We will leverage mouse models and critically define the roles of these two cell types. In Aim 2, we will examine regulatory mechanisms in allergic immune responses by focusing on newly identified T follicular regulatory (Tfr) cells. Both a mouse genetic approach and a prospective study in humans will be used to understand the roles of this new cell type. In Aim 3, we will address the fundamental question of why certain environmental factors serve as potent allergens by studying Alternaria, which is implicated in allergic diseases. In collaboration with an Alternaria expert, Dr. Christopher Lawrence, we will take a robust fungal functional genomic approach. Together, the studies in these aims will define the central mechanisms underlying the development and regulation of type 2 immunity to airborne allergens and will provide an immunologic explanation regarding various clinical phenotypes of allergic diseases. Ultimately, these studies will characterize key cellular pathway(s) and molecule(s) involved in allergic immune responses, allowing identification of critical targets for development of novel therapeutic strategies to treat or to prevent asthma and allergic diseases.

项目总结/文摘