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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：
10614529
负责人：
Maria CECILIA BERIN
金额：
$ 60.37万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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 2025-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10614529
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 CD4 Positive T Lymphocytes Cell Compartmentation Cell Maintenance Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Child Circulation 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 IgE介导的食物过敏是一种常见疾病，在美国约有1/13的儿童受到影响。对许多人来说，这是一种终身疾病，对生活质量有显著损害，并且没有FDA批准的治疗。虽然 IgE是食物过敏的病理生理学的中心，IgE的维持知之甚少，并且是食物过敏的关键。开发真正能改善疾病的治疗方法。我们已经证明，小鼠体内IgE的维持需要从CD 4 + T细胞产生IL-4，并阻断人类IL-4/13信号传导，表明IgE需要持续产生Th 2细胞因子以维持。小鼠的IgE记忆包含在一个群体中，抗原特异性IgG+记忆细胞，在T细胞的帮助下不断更新短暂的IgE+浆细胞库。目前缺乏关于人体IgE产生的细胞基础的相应信息。我们假设记忆性IgG+ B细胞是人体内主要的B细胞亚群，控制T细胞的帮助。我们已经确定了Th 2细胞因子产生的CD 4 + T细胞的显著异质性，食物过敏个体，包括常规Th 2细胞、致病性效应Th 2细胞（peTh 2）和滤泡性T细胞辅助2型（Tfh 2）细胞。我们认为peth 2细胞在肠组织中富集，在那里它们可以支持从变应原特异性IgG记忆B细胞向IgE的类别转换。我们认为Tfh 2细胞富含粘膜淋巴组织（扁桃体），它们支持幼稚和记忆B细胞的类别转换，后者是高亲和力IgE的来源。此外，我们提出，CD 27+常规Th 2细胞是一种通过淋巴组织中的局部线索维持Tfh 2和peth 2细胞池的记忆库和粘膜。在这个多PI提案中，将食物过敏中的T细胞和B细胞专业知识结合在一起，我们将使用扁桃体、胃肠道活检和IgE患者的血液来检验这些假设，介导的食物过敏。了解IgE-1背景下CD 4 + Th 2亚群的维持和功能介导的食物过敏将允许我们设计用于治疗食物过敏的疾病修饰免疫疗法。