The role of follicular helper T cell cytokines in the IgE response

滤泡辅助 T 细胞细胞因子在 IgE 反应中的作用

基本信息

批准号：
8794264
负责人：
EDWARD HERMAN
金额：
$ 4.81万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2016-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8794264
关键词：
Adoptive Transfer Affinity Allergens Allergic Allergic Disease Anatomy Antibodies Antibody Affinity Antigens Area Asthma B-Lymphocytes Basic Science Binding Biological Assay CD4 Positive T Lymphocytes Cell Degranulation Cell Differentiation process Cells Cellular Immunology Chronic Clinical Cloning Collaborations Complex Computational Biology Data Data Analyses Development Disease Enzyme-Linked Immunosorbent Assay Extrinsic asthma Flow Cytometry Foundations Health Helper-Inducer T-Lymphocyte Human Hypersensitivity IgE IgG1 IgG4 Immune Immunization Immunoglobulin Class Switching Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Individual Infection Inflammatory Inflammatory Response Interleukin-4 Intervention Kinetics Lead Learning Location Lymphoid Measures Mediating Mentorship MicroRNAs Modeling Molecular Mucous body substance Mutant Strains Mice Organ Pathogenesis Pathway interactions Patients Pattern Phenotype Physicians Plant Roots Population Prevalence Process Production Public Health Regulation Regulatory Pathway Reporter Genes Research Research Training Role Scientist Sequence Analysis Set protein Severities Signal Transduction Staging Staining method Stains Structure of germinal center of lymph node Symptoms System T-Lymphocyte T-Lymphocyte Subsets TNFSF5 gene Techniques Testing Therapeutic Intervention Time Training Translating Work Writing anti-IgE base career clinically relevant clinically significant constriction cytokine effective therapy environmental allergen enzyme linked immunospot assay eosinophil improved in vivo mast cell mouse model next generation sequencing novel therapeutics pathogen receptor response skills technique development therapy development transcription factor

项目摘要

DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease and is frequently associated with an allergic component. Asthma poses a major public health burden. Prevalence of this disease has increased greatly over the last four decades yet many questions regarding the basic mechanisms that lead to this disease remain unanswered. High-affinity, allergen-specific IgE antibodies are strongly implicated in the pathogenesis of allergic asthma, as are pathways involved in IgE production such as signaling by interleukin-4 (IL-4). A unique subset of CD4 T cells termed follicular helper T cells (Tfh cells) are present in the germinal center (GC) where they provide critical help in the production of high-affinity antibodies as well as isotype class switching, including to IgE, via production of IL-4. Tfh cells also secrete IL-21,a cytokine that represses switching to IgE, suggesting a complex relationship between Tfh cells, cytokine production, and isotype switching. This proposal seeks to test the hypothesis that Tfh cells regulate the production of IL-4 and IL-21 independently to coordinate the GC response and evoke IgE production. Three specific aims are proposed to interrogate this hypothesis. The first aim will investigate the relationship between Tfh cells and the humoral response in vivo by defining subpopulations of Tfh cells by their cytokine secretion on the basis of intracellular staining as well as using mutant mice expressing fluorescent reporter genes. The composition of these populations will be measured in relation to antibody titer and the GC response in several models of infection and immunization and across time and anatomical location. The second aim is to directly connect different subpopulations of cytokine-secreting Tfh cells with the GC B cells they are interacting with, and to utilize an adoptive transfer system to test the function of these individual populations. In the third aim, regulatory networks controlling cytokin production will be determined using advanced techniques in next-generation sequencing and computational biology. Altogether, this work will further clarify the mechanism by which Tfh cells control allergy- inducing IgE antibodies and in doing so will identify targets for disrupting this process. In addition, this application details the applicant's training plan including research mentorship, advanced coursework, training in new techniques, and development of skills in scientific professionalism, writing, and presentation of data. The development of new treatments for major diseases like asthma depends on projects like this one which translate clinical problems into basic research questions. The research and training outlined in this application will prepare the applicant to pursue a career in the conduct of clinically relevant research as an independent physician scientist.

描述（由申请人提供）：哮喘是一种慢性炎症性疾病，通常与过敏因素有关。哮喘造成重大的公共卫生负担。在过去四十年中，这种疾病的患病率大大增加，但有关导致这种疾病的基本机制的许多问题仍未得到解答。高亲和力、过敏原特异性 IgE 抗体与过敏性哮喘的发病机制密切相关，参与 IgE 产生的途径（例如白细胞介素 4 (IL-4) 信号传导）也是如此。生发中心 (GC) 中存在一种独特的 CD4 T 细胞亚群，称为滤泡辅助 T 细胞 (Tfh 细胞)，它们在高亲和力抗体的产生以及同种型类别转换（包括 IgE）方面提供关键帮助，通过IL-4的产生。 Tfh 细胞还分泌 IL-21，这是一种抑制向 IgE 转换的细胞因子，表明 Tfh 细胞、细胞因子产生和同种型转换之间存在复杂的关系。该提案旨在检验 Tfh 细胞独立调节 IL-4 和 IL-21 的产生以协调 GC 反应并引发 IgE 产生的假设。提出了三个具体目标来质疑这一假设。第一个目标是通过基于细胞内染色的细胞因子分泌来定义 Tfh 细胞亚群以及使用表达荧光报告基因的突变小鼠来研究 Tfh 细胞与体内体液反应之间的关系。这些群体的组成将根据几种感染和免疫模型中的抗体滴度和 GC 反应以及跨时间和解剖位置的关系进行测量。第二个目标是将分泌细胞因子的 Tfh 细胞的不同亚群与它们与 GC B 细胞相互作用，并利用过继转移系统来测试这些个体群体的功能。第三个目标是利用下一代测序和计算生物学的先进技术来确定控制细胞因子产生的调控网络。总而言之，这项工作将进一步阐明 Tfh 细胞控制过敏诱导 IgE 抗体的机制，并在此过程中确定破坏这一过程的目标。此外，该申请还详细说明了申请人的培训计划，包括研究指导、高级课程、新技术培训以及科学专业、写作和数据呈现技能的发展。哮喘等重大疾病新疗法的开发取决于像这样的项目，它将临床问题转化为基础研究问题。本申请中概述的研究和培训将使申请人为作为独立医师科学家从事临床相关研究的职业做好准备。