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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.

概括 IgE 介导的食物过敏是一种常见疾病，影响美国大约三分之一的儿童。对于许多人来说，这是一种终生疾病，会严重损害生活质量，且尚无 FDA 批准的治疗方法。虽然 IgE 是食物过敏病理生理学的核心，人们对 IgE 的维持知之甚少，但 IgE 的维持是食物过敏的关键。开发真正改变疾病的治疗方法。我们已经证明，维持小鼠 IgE 需要 CD4+ T 细胞产生 IL-4，并阻断人类中的 IL-4/13 信号传导表明 IgE 需要持续产生 Th2 细胞因子以维持维持。小鼠的 IgE 记忆包含在以下群体中抗原特异性 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。目前缺乏关于人类 IgE 产生的细胞基础的相应信息。我们假设记忆 IgG+ B 细胞是人类主要的 B 细胞亚群，过敏原特异性 IgE 源自该亚群对T细胞的控制有帮助。我们已经发现来自 Th2 细胞因子的 CD4+ T 细胞产生显着的异质性。食物过敏个体，包括常规 Th2 细胞、致病效应 Th2 细胞 (peTh2) 和滤泡 T 2 型辅助细胞 (Tfh2)。我们认为，peTh2 细胞在肠道组织中富集，可以支持从过敏原特异性 IgG 记忆 B 细胞类别转换为 IgE。我们认为 Tfh2 细胞富含粘膜淋巴组织（扁桃体），它们支持幼稚 B 细胞和记忆 B 细胞的类别转换，其中后者是高亲和力 IgE 的来源。此外，我们认为 CD27+ 常规 Th2 细胞是记忆库，通过淋巴组织中的局部线索维持 Tfh2 和 peTh2 细胞库和粘膜，分别。在这项多 PI 提案中，汇集了 T 细胞和 B 细胞在食物过敏方面的专业知识，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- 背景下 CD4+ Th2 亚群的维持和功能介导的食物过敏将使我们能够设计疾病修饰免疫疗法来治疗食物过敏。