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

• 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
• 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

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，经常与过敏成分有关。哮喘造成了重大的公共卫生负担。在过去的四十年中，这种疾病的患病率大大增加，但有关导致该疾病的基本机制的许多问题仍未得到解决。高亲和力，过敏原特异性IgE抗体与过敏性哮喘的发病机理有着强烈的影响，以及与INTRUEUKIN-4（IL-4）相关的IgE产生途径（IL-4）。在生发中心（GC）中存在称为卵泡辅助T细胞（TFH细胞）的CD4 T细胞的独特子集，它们通过生产IL-4的生产提供了在高亲和力抗体以及包括IGE在内的同类类转换的关键帮助。 TFH细胞还分泌IL-21，这是一种抑制切换到IgE的细胞因子，表明TFH细胞，细胞因子产生和同型切换之间存在复杂的关系。该提案旨在检验以下假设：TFH细胞独立地调节IL-4和IL-21的产生，以协调GC响应并引起IgE产生。提出了三个特定的目标来审问这一假设。第一个目的将通过基于细胞内染色以及使用表达荧光报道基因的突变小鼠来确定TFH细胞的亚群来研究TFH细胞与体内体液反应之间的关系。这些种群的组成将根据抗体滴度以及几种感染和免疫模型以及时间和解剖位置的GC反应进行测量。第二个目的是直接将分泌细胞因子分泌TFH细胞的不同亚群与 他们正在与之相互作用的GC B单元，并利用过继转移系统来测试这些单个人群的功能。在第三个目标中，控制细胞因子产生的调节网络将使用下一代测序和计算生物学中的先进技术确定。总而言之，这项工作将进一步阐明TFH细胞控制过敏的IgE抗体的机制，并在这样做将确定破坏此过程的目标。此外，此应用程序详细介绍了申请人的培训计划，包括研究指导，高级课程，新技术的培训以及科学专业，写作和数据介绍方面的技能。诸如哮喘之类的主要疾病的新疗法的发展取决于将临床问题转化为基础研究问题的项目。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的临床相关研究从事职业做好准备。