The Role of TNF in Breaking B Cell Tolerance

TNF 在破坏 B 细胞耐受性中的作用

基本信息

批准号：
10188437
负责人：
Tam D Quach
金额：
$ 12.77万
依托单位：
FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
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：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10188437
关键词：
Address Affect Affinity Age Agonist Amyloid fibers Anti-Inflammatory Agents Antibodies Antibody Formation Antibody-Producing Cells Antigen-Antibody Complex Antigens Antinuclear Antibodies Autoantibodies Autoimmune Autoimmunity B cell differentiation B-Cell Activation B-Lymphocyte Subsets B-Lymphocytes Binding Biological CD22 gene Cells Chromatin Clinical Clinical Research Computational Biology Computer Models Data Defect Demyelinating Diseases Development Development Plans Disease Drug usage Education Educational workshop Environment Escherichia coli Faculty Follicular Dendritic Cells Foundations Future Generations Goals Grant Homeostasis Human IL17 gene Immune response Immune system Immunologist In Vitro Individual Institutes Interleukin-17 Knowledge Ligands Lupus Mediating Medical Research Mentors Methodology Modeling Mus Opportunistic Infections Pathogenicity Pathway interactions Patient Selection Patients Pharmaceutical Preparations Phenotype Play Postdoctoral Fellow Pristane Process Production Psoriasis RNA Reagent Regulation Research Research Activity Research Personnel Research Project Grants Resources Rheumatoid Arthritis Role SLEB1 gene Sampling Self Tolerance Signal Transduction Source Stimulus Structure Structure of germinal center of lymph node System Systemic Lupus Erythematosus T-Lymphocyte TLR2 gene TNF gene TNFRSF1A gene TNFRSF1B gene Technology Testing Training Training Activity United States Vasculitis Work attenuation autoreactive B cell autoreactivity career development chronic autoimmune disease cohort cytokine design drug development effective therapy effector T cell experience immunoregulation improved individual patient inhibitor/antagonist insight instructor interleukin-21 member mouse model mutational status next generation sequencing novel personalized medicine predictive modeling prevent response restoration safe patient side effect skills

项目摘要

Dr. Quach's central goal is to acquire new skills that will establish her as a systems immunologist. The proposed research combines murine and human studies to identify mechanisms by which TNF deficiency breaks tolerance. The gained knowledge will guide future efforts in designing personalized medicine for autoimmune patients. Candidate: Dr. Quach is an instructor at the Feinstein Institute for Medical Research (FIMR). Through her Ph.D and post-doctoral work, she focused on the development and regulation of B cells in humans. The proposed career development plan will build upon her previous experience with four training goals to enhance her trajectory toward becoming an independent investigator: 1) gain expertise in utilizing mouse models; 2) become proficient in computational biology; 3) gain insights into conducting clinically oriented research projects, and 4) build a foundation of data and methodologies to generate predictive models. Mentors/Environment: Dr. Quach and her mentor, Dr. Anne Davidson, have assembled a strong team of advisors and collaborators to guide her through the proposed training and research activities. The proposed project utilizes the intellectual, research and clinical facilities available at the FIMR and the resources available through her external advisors and collaborators, Dr. Steven Kleinstein and Dr. Inaki Sanz. FIMR is committed to support junior faculty members through internal grants and opportunities for networking and education. Dr. Quach will attend national seminars/workshops when optimal training is not available locally. Research: The induction of autoantibody and autoimmunity in patients treated with TNF inhibitors (TNFi) is well- known; however, the mechanism by which TNFi induce breach of B cell tolerance is yet to be determined. In humans, TNFi affect B and T cell homeostasis via disruption of germinal center (GC) formation which is pivotal for high affinity antigen-specific antibody production and negative selection of autoreactive B cells. Similarly, in mice, TNF signaling deficiency prevents GC formation, induces TFH and CD4+IL-17 producing cell expansion, and alters autoantibody profiles. This study proposes that TNF deficiency, together with a second inducing stimulus, compromises GC B cell selection via reduction of negative GC B cell signaling and enhancement of T effector cell activities. To test this hypothesis, the first aim utilizes TNF deficient mice of 2 different backgrounds, autoreactive Sle1.TNF-/- mice induced with a TLR9 agonist and NZM2328.TNFR1/2 double deficient mice, to determine the mechanism for the signaling defect in GC B cells that alters B cell selection, and how T cells help to enhance this process. The second aim will address similar questions in TNFi treated patients using a novel fluorescent reagent to detect and isolate ANA reactive B cells combined with next generation sequencing technology. A combination of phenotyping and functional studies is used to determine T cells' influences. The results from this study will elucidate the effects of TNFi on regulating B cell tolerance and improve our understanding of how the immune system regulates B cell tolerance when GC formation is abnormal.

Quach 博士的中心目标是获得新技能，使她成为一名系统免疫学家。拟议的研究结合了小鼠和人类研究，以确定 TNF 缺乏破坏耐受性的机制。所获得的知识将指导未来为自身免疫患者设计个性化医疗的努力。候选人：Quach 博士是范斯坦医学研究所 (FIMR) 的讲师。通过她的博士学位在博士后工作中，她专注于人类 B 细胞的发育和调节。拟议的职业发展计划将以她之前的经验为基础，通过四个培训目标来提升她的发展轨迹成为一名独立研究者：1）获得利用小鼠模型的专业知识； 2）变得熟练计算生物学； 3) 深入了解开展临床导向的研究项目，以及 4) 建立生成预测模型的数据和方法的基础。导师/环境：Quach 博士和她的导师 Anne Davidson 博士组建了一支强大的团队顾问和合作者指导她完成拟议的培训和研究活动。拟议的项目利用 FIMR 的知识、研究和临床设施以及可用资源通过她的外部顾问和合作者 Steven Kleinstein 博士和 Inaki Sanz 博士。 FIMR 致力于通过内部拨款以及网络和教育机会来支持初级教员。博士。当当地无法提供最佳培训时，Quach 将参加国家研讨会/讲习班。研究：使用 TNF 抑制剂 (TNFi) 治疗的患者可很好地诱导自身抗体和自身免疫。已知；然而，TNFi 诱导 B 细胞耐受破坏的机制尚未确定。在在人类中，TNFi 通过破坏至关重要的生发中心 (GC) 形成来影响 B 和 T 细胞稳态用于高亲和力抗原特异性抗体生产和自身反应性 B 细胞的阴性选择。同样，在小鼠中，TNF 信号传导缺陷阻止 GC 形成，诱导 TFH 和 CD4+IL-17 产生细胞扩增，并改变自身抗体谱。这项研究提出，TNF 缺乏以及第二种诱导因素刺激，通过减少阴性 GC B 细胞信号传导和增强 T 来损害 GC B 细胞选择效应细胞活动。为了检验这一假设，第一个目标是利用 2 种不同背景的 TNF 缺陷小鼠，用 TLR9 激动剂和 NZM2328.TNFR1/2 双缺陷小鼠诱导自身反应性 Sle1.TNF-/- 小鼠，确定 GC B 细胞信号缺陷改变 B 细胞选择的机制，以及 T 细胞如何提供帮助来加强这个过程。第二个目标将使用一种新颖的方法解决 TNFi 治疗患者中的类似问题荧光试剂结合下一代测序检测和分离 ANA 反应性 B 细胞技术。结合表型分析和功能研究来确定 T 细胞的影响。这这项研究的结果将阐明 TNFi 对调节 B 细胞耐受性的影响，并改善我们的了解当 GC 形成异常时免疫系统如何调节 B 细胞耐受性。