Antibody Mediated Mechanisms of Immune Modulation in Tuberculosis

结核病免疫调节的抗体介导机制

• 批准号: 9294245
• 负责人: Lenette Lu
• 金额: $ 20.19万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-10 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9294245
• 关键词: Address; Affinity; Animal Model; Antibodies; Antibody Response; Antigen Presentation; Antigens; Biological Assay; Cells; Cellular Immunity; Clinical; Communicable Diseases; Complement Activation; Coupled; Diagnostic; Disease; Disease model; Fc Receptor; Fc domain; Fortune; Foundations; General Hospitals; Human; Humoral Immunities; Immune; Immune response; In Vitro; Individual; Infection; Inflammasome; Institutes; Interleukin-1 beta; Kinetics; Massachusetts; Mediating; Medicine; Mentors; Modeling; Modification; Mycobacterium tuberculosis; Phagocytosis; Physicians; Physiological; Play; Population; Positioning Attribute; Process; Program Development; Proteome; Public Health Schools; Recruitment Activity; Research; Research Training; Role; Scientist; Serological; Specificity; Structure; System; Techniques; Therapeutic; Translating; Translations; Tuberculosis; Vaccine Design; Vaccines; Vision; Work; antimicrobial; base; burden of illness; career development; cohort; cytotoxicity; design; experience; experimental study; glycosylation; immunoregulation; instructor; knock-down; macrophage; medical schools; mouse model; neutralizing antibody; novel vaccines; pathogen; receptor; receptor binding; response; skills; tool; tuberculosis immunity

Project Summary/Abstract This proposal presents a five year research career development program focused on the study of antibody mediated immune modulation in tuberculosis to expand the breadth and depth of understanding the role of humoral immunity in this disease. The candidate is currently an Instructor of Medicine at Harvard Medical School in the Division of Infectious Diseases at the Massachusetts General Hospital. The outlined proposal builds on the candidate's previous research and clinical experience in host pathogen interactions by integrating two new domains of expertise represented by her mentor team of Drs Sarah Fortune and Galit Alter at the Harvard School of Public Health and the Ragon Institute of MGH, MIT and Harvard: tuberculosis and antibody mediated mechanisms of innate immune effector functions. The proposed experiments and didactic work will position the candidate with a unique set of cross disciplinary skills that will enable her transition to independence as a physician scientist in antibody mediated host pathogen interactions in tuberculosis. One third of the world's population carries the burden of tuberculosis (TB). Efforts to reduce this burden have been hindered by the lack effective diagnostics and a protective vaccine underpinned by gaps in the understanding of the immune response in TB disease. While cellular immunity is important, the antibody (Ab) or humoral landscape is poorly understood. Ab function is determined by the combination of antigen specificity via the Fab and ability to recruit functional responses via the Fc domain. Ab Fc mediated recruitment of cellular responses is a promising underexplored potential for immune control. The foundation for this proposal is based on preliminary studies evaluating differences in antibody profiles from a systems serological approach in a cohort of individuals with latent and active TB that suggest a potential protective role for antibodies in TB disease. How exactly antibodies might function in this context and its physiological relevance are questions that this proposal begins to address. More specifically, the aims of this proposal are 1: Define the antigen specificity of functional M. tuberculosis (Mtb) specific antibodies, 2: Dissect the role for Fc/FcR mediated intracellular Mtb restriction and 3: Identify the macrophage effector mechanisms through which Ab restrict intracellular Mtb. The scientific objective of this proposal is to begin to define the Ab Fab and Fc features with the capacity to mediate effector function against intracellular Mtb with the vision of targeted transition into an appropriate animal model to generate hypotheses that inform the direction and design of subsequent human studies to expand the repertoire for immune correlates/diagnostics and rational vaccine design.

项目概要/摘要 该提案提出了一个专注于抗体研究的五年研究职业发展计划 介导的免疫调节在结核病中的作用扩大了理解的广度和深度 本病的体液免疫。该候选人目前是哈佛医学院的医学讲师 学校位于马萨诸塞州总医院传染病科。概述的提案 基于候选人之前在宿主病原体相互作用方面的研究和临床经验，通过整合 她的导师团队 Sarah Fortune 博士和 Galit Alter 博士代表了两个新的专业领域 哈佛大学公共卫生学院和麻省总医院、麻省理工学院和哈佛大学的拉根研究所：结核病和抗体 先天免疫效应功能的介导机制。拟议的实验和教学工作将 为候选人提供一套独特的跨学科技能，使她能够过渡到 作为一名医师科学家，在抗体介导的结核病宿主病原体相互作用方面具有独立性。 世界上三分之一的人口患有结核病（TB）。减轻这一负担的努力已 因缺乏有效的诊断方法和保护性疫苗而受到阻碍 了解结核病的免疫反应。虽然细胞免疫很重要，但抗体 (Ab) 或者对体液景观知之甚少。 Ab功能由抗原特异性组合决定 通过 Fab 和通过 Fc 结构域招募功能反应的能力。 Ab Fc 介导的细胞募集 反应是免疫控制的一个有待开发的有前途的潜力。本提案的基础是 初步研究评估了系统血清学方法中抗体谱的差异 潜伏性和活动性结核病患者队列表明抗体对结核病具有潜在的保护作用 疾病。抗体在这种情况下究竟如何发挥作用及其生理相关性仍然是个问题 本提案开始解决这一问题。更具体地说，该提案的目标是 1：定义抗原 功能性结核分枝杆菌 (Mtb) 特异性抗体的特异性，2：剖析 Fc/FcR 介导的作用 细胞内 Mtb 限制和 3：确定 Ab 限制的巨噬细胞效应机制 细胞内结核分枝杆菌。该提案的科学目标是开始定义 Ab Fab 和 Fc 特征 介导针对细胞内 Mtb 的效应功能的能力，并有针对性地转变为 适当的动物模型来产生假设，为后续人类的方向和设计提供信息 扩大免疫相关/诊断和合理疫苗设计范围的研究。