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：
10447094
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/10447094
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 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博士的核心目标是获得将她确立为系统免疫学家的新技能。提议研究结合了鼠类和人类研究，以识别TNF缺乏症破坏耐受性的机制。获得的知识将指导未来为自身免疫性患者设计个性化医学的努力。候选人：Quach博士是Feinstein医学研究所（FIMR）的讲师。通过她的博士学位和博士后工作，她专注于人类B细胞的发展和调节。提议职业发展计划将基于她以前的四个培训目标以增强她的轨迹的经验成为一个独立研究者：1）在利用小鼠模型方面获得专业知识； 2）精通在计算生物学中； 3）获得有关进行临床研究项目的见解，4）建立一个数据和方法的基础，以生成预测模型。导师/环境：Quach博士和她的导师Anne Davidson博士组建了一个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。提议项目利用FIMR可用的知识，研究和临床设施以及可用的资源通过她的外部顾问和合作者史蒂文·克莱恩斯坦（Steven Kleinstein）和伊纳基·桑兹（Inaki Sanz）博士。 FIMR致力于通过内部赠款和网络和教育的机会来支持初级教师。博士当最佳培训在当地进行时，Quach将参加全国研讨会/研讨会。研究：用TNF抑制剂（TNFI）的患者诱导自身抗体和自身免疫性是很好的已知但是，TNFI诱导B细胞耐受性的机制尚未确定。在人类，TNFI通过破坏生发中心（GC）形成而影响B和T细胞稳态，这是关键用于高亲和力抗原特异性抗体的产生和自动反应性B细胞的阴性选择。同样，在小鼠，TNF信号缺乏可防止GC的形成，诱导TFH和CD4+IL-17产生细胞膨胀，并改变自身抗体概况。这项研究提出TNF缺乏症以及第二次诱导刺激，通过减少负GC B细胞信号传导和T的增强来损害GC B细胞的选择效应细胞活动。为了检验这一假设，第一个目标利用了2种不同背景的TNF缺乏小鼠，用TLR9激动剂和NZM2328.TNFR1/2双缺陷小鼠诱导的自动反应性SLE1.TNF - / - 小鼠至确定改变B细胞选择的GC B细胞中信号传导缺陷的机制，以及T细胞如何帮助增强此过程。第二个目标将使用新颖的患者解决类似的问题荧光试剂检测和分离出ANA反应性B细胞与下一代测序技术。表型和功能研究的组合用于确定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了解当GC形成异常时，免疫系统如何调节B细胞耐受性。