Comprehensive analysis of human adaptive immune receptors to elucidate correlates of Epstein-Barr virus disease suppression

全面分析人类适应性免疫受体以阐明 Epstein-Barr 病毒疾病抑制的相关性

• 批准号: 9212615
• 负责人: Brandon James DeKosky
• 金额: $ 36.98万
• 依托单位: UNIVERSITY OF KANSAS LAWRENCE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-19 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9212615
• 关键词: Address; Antibodies; B cell repertoire; B-Lymphocytes; Burkitt Lymphoma; CD8B1 gene; Cells; Chronic; Clinical; Clinical Research; Convalescence; Cost Effectiveness Analysis; Data; Data Analyses; Data Set; Development; Disease; EBV-associated disease; Ensure; Epstein-Barr Virus Infections; Exhibits; Fatigue; Future; Goals; Herpesviridae; Herpesviridae Infections; Hodgkin Disease; Human; Human Herpesvirus 4; Immune; Immune System Diseases; Immune response; Immunocompetent; Immunologic Receptors; Incidence; Individual; Infection; Infectious Mononucleosis; Intervention; Knowledge; Large-Cell Immunoblastic Lymphoma; Lead; Lymphoproliferative Disorders; Machine Learning; Malignant Neoplasms; Methods; Molecular; Multiple Sclerosis; Nasopharynx Carcinoma; Oncogenic; Patients; Phase; Population; Prevention; Preventive; Primary Infection; Public Health; Questioning individuals; Receptors, Antigen, B-Cell; Recovery; Research Personnel; Risk; Sampling; Serum; Severities; Severity of illness; Stomach Carcinoma; Symptoms; T cell response; T-Cell Receptor; T-Lymphocyte; Techniques; Technology; Teenagers; Testing; Therapeutic; Vaccine Design; Vaccines; Viral; Virus Diseases; Work; abstracting; adaptive immunity; base; career; cohort; cost; design; disorder control; human disease; immune function; insight; multiple sclerosis patient; neutralizing monoclonal antibodies; next generation; novel; novel therapeutics; novel vaccines; pathogen; pressure; prevent; prospective; research study; response; therapeutic development; therapeutic vaccine; treatment strategy; vaccine development; vaccine trial; virology; young adult

Project Summary/Abstract This project will develop a new technological approach for the comprehensive analysis of adaptive immune responses, which holds the potential to catalyze new strategies to prevent and treat disease. Here we will apply immune profiling techniques recently invented by the PI to investigate the mechanisms of Epstein-Barr virus (EBV) adaptive immune control in clinical cohorts of infected patients. EBV is a highly prevalent pathogen infecting >90% of the world’s population. Primary EBV infection often causes infectious mononucleosis (IM) and long-term sequelae include numerous malignancies, lymphoproliferative disorders, and a strong association with multiple sclerosis. No EBV vaccine is approved to date, and the molecular mechanisms of immune protection from EBV-associated diseases are unclear. Unfortunately, prior technical barriers in high- throughput immune profiling methods have prevented a comprehensive understanding of adaptive immune protection against EBV diseases. A technological approach that identifies the critical features of EBV immune protection will advance new solutions for vaccine and therapeutic development. Therefore, we developed an experimental pipeline to enable rapid and cost-effective analysis of B- and T-cell responses to EBV that is scalable to dozens of human patients per experiment. We hypothesize that a comprehensive B- and T-cell analysis of carefully selected patient cohorts that either can or cannot suppress symptomatic infection will reveal function-based correlates of EBV control. To test this hypothesis, we will apply quantitative immune profiling technologies to analyze cryopreserved longitudinal samples from recently completed prospective clinical studies of IM. Patient samples in our cohort span pre- and post-infection through convalescence and encompass the full range of clinical IM severity scores (from 0, asymptomatic primary infection, to 6, essentially bedridden with IM). Immune profile data will be used to establish adaptive immune correlates of IM disease severity. In addition, we will analyze immune responses in apparently immunocompetent patients with chronic active EBV (CAEBV) disease, or patients who do not adequately suppress EBV infection, to gain insight regarding adaptive immune function and dysfunction in CAEBV. Finally, we will develop a new computational toolkit to rapidly identify immune correlates from high-throughput datasets. Successful completion of this project will constitute the first comprehensive functional B- and T-cell receptor analysis in a human clinical cohort. Our efforts will provide a repertoire-scale, mechanistic understanding of adaptive immunity to EBV and suggest new strategies for treatment and prevention of EBV-associated diseases. Our long-term goal is to develop human immune profiling techniques as a platform approach to accelerate the rational design of vaccines and therapeutics against pathogens of high public health importance, beginning with EBV.

项目摘要/摘要 该项目将开发一种新的技术方法，用于对自适应免疫的全面分析 反应，这有可能催化预防和治疗疾病的新策略。我们会在这里 应用PI最近发明的免疫分析技术来研究Epstein-Barr的机制 感染患者临床队列中的病毒（EBV）自适应免疫控制。 EBV是一种高度普遍的病原体 感染> 90％的世界人口。原发性EBV感染通常会引起感染性单核细胞增多症（IM） 和长期后遗症包括许多恶性肿瘤，淋巴增生性疾病和强烈 与多发性硬化症相关。迄今未批准EBV疫苗，并且分子机制 不清楚与EBV相关疾病的免疫保护尚不清楚。不幸的是，高级技术障碍 吞吐量免疫蛋白药物阻止了对适应性免疫的全面理解 防止EBV疾病。一种识别EBV免疫的关键特征的技术方法 保护将推进疫苗和治疗开发的新解决方案。因此，我们开发了 实验馈线可以对B-和T细胞对EBV的响应进行快速且具有成本效益的分析 每个实验可扩展到数十名人类患者。我们假设一个全面的B和T细胞 分析精心挑选的患者队列可以或无法抑制症状感染的分析 揭示基于功能的EBV控制的相关性。为了检验该假设，我们将采用定量免疫 分析技术以分析来自最近完成的前瞻性的冷冻保存纵向样品 IM的临床研究。通过康复后感染前和感染后的患者样本， 涵盖了一系列临床IM严重程度评分（从0，无症状的原发性感染到6 本质上是与IM卧床不起的。免疫轮廓数据将用于建立IM的适应性免疫相关性 疾病的严重程度。此外，我们还将分析显然是免疫能力的患者的免疫调查 慢性活性EBV（CAEBV）疾病，或不充分抑制EBV感染的患者 CAEBV中有关适应性免疫功能和功能障碍的见解。最后，我们将开发一个新的 计算工具包快速识别来自高通量数据集的免疫相关性。成功的 该项目的完成将构成A 人类临床队列。我们的努力将提供对适应性的曲目规模的机械理解 对EBV的免疫力，并提出了治疗和预防与EBV相关疾病的新策略。我们的 长期目标是开发人类免疫专长技术作为一种平台方法来加速 疫苗的合理设计和针对高公共健康重要性的病原体的治疗，开始 与EBV。