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Heterogeneity of T cell phenotype and function in food allergy

食物过敏中 T 细胞表型和功能的异质性

基本信息

批准号：
10392434
负责人：
Maria CECILIA BERIN
金额：
$ 57.81万
依托单位：
ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-15 至 2022-08-15
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10392434
关键词：
Address Affect Affinity Allergen Immunotherapy Allergens Allergic Allergy to eggs Allergy to peanuts Antibodies Antigens B-Lymphocyte Subsets B-Lymphocytes BLR1 gene Biopsy Blood Blood Circulation CD4 Positive T Lymphocytes Cell Compartmentation Cell Maintenance Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Child Cues Disease Duodenum FDA approved Flow Cytometry Food Food Hypersensitivity Functional disorder Generations Half-Life Heterogeneity Human IL4 gene IL5 gene IL9 gene IgE Immunoglobulin A Immunoglobulin Class Switching Immunoglobulin G Immunoglobulin M Immunotherapy Impairment In Vitro Individual Interleukin-13 Interleukin-4 Intervention Intestines Location Lymphoid Tissue Maintenance Mediating Memory Memory B-Lymphocyte Mucous Membrane Mus Oral Outcome Outcomes Research Pathogenicity Patients Phenotype Plasma Cells Population Production Quality of life Regulation Regulatory T-Lymphocyte Research Role Signal Transduction Site Source Specimen Supporting Cell System T memory cell T-Lymphocyte T-Lymphocyte Subsets TNFSF5 gene Testing Th2 Cells Time Tissues Tonsil Up-Regulation Work cytokine design effector T cell food allergen food challenge gastrointestinal high dimensionality interleukin-13 receptor lymph nodes neutralizing antibody omalizumab pathogen peripheral blood response single-cell RNA sequencing therapeutic target

项目摘要

SUMMARY IgE-mediated food allergy is a common disease affecting approximately 1 in 13 children in the USA. For many, this is a lifelong disease with significant impairment in quality of life and no FDA-approved treatment. Although IgE is central to the pathophysiology of food allergy, the maintenance of IgE is poorly understood and is key to developing treatments that are truly disease modifying. We have shown that maintenance of IgE in mice requires IL-4 production from CD4+ T cells, and blocking IL-4/13 signaling in humans demonstrates that IgE requires continual Th2 cytokine production for maintenance. IgE memory in mice is contained within a population of antigen-specific IgG+ memory cells that continually renew the short-lived IgE+ plasma cell pool with T cell help. There is a lack of corresponding information on the cellular basis of IgE production in humans. We hypothesize that memory IgG+ B cells are the main B cell subset in humans from which allergen-specific IgE is derived under control of T cell help. We have identified significant heterogeneity in Th2 cytokine producing CD4+ T cells from food allergic individuals, including conventional Th2 cells, pathogenic effector Th2 cells (peTh2), and T follicular helper type-2 (Tfh2) cells. We propose that peTh2 cells are enriched in intestinal tissues where they can support class-switch to IgE from allergen-specific IgG memory B cells. We propose that Tfh2 cells are enriched in mucosal lymphoid tissues (tonsils) where they support class switch from naïve and memory B cells, with the latter being the source of high-affinity IgE. Furthermore, we propose that CD27+ conventional Th2 cells are a reservoir of memory that maintain the pool of Tfh2 and peTh2 cells through local cues in the lymphoid tissues and mucosa, respectively. In this multi-PI proposal bringing together T cell and B cell expertise in food allergy, we will test these stated hypotheses using tonsil, gastrointestinal biopsies, and blood from patients with IgE- mediated food allergy. Understanding the maintenance and function of CD4+ Th2 subsets in the context of IgE- mediated food allergy will allow us to design disease modifying immunotherapies for the treatment of food allergy.

总结