Targeted in vivo perturbation for dissecting tissue immune responses

用于剖析组织免疫反应的靶向体内扰动

• 批准号: 10594543
• 负责人: PHILIP L DE JAGER
• 金额: $ 28.04万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594543
• 关键词: 2019-nCoV; Activities of Daily Living; Address; Antibodies; Antibody Response; Antigens; B-Lymphocytes; Biological Assay; Biological Models; Biology; COVID-19 booster; COVID-19 risk; COVID-19 vaccination; COVID-19 vaccine; Cell physiology; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Circulation; Clinical; Complex; Cytomegalovirus; Disease; Elements; Enrollment; Ensure; Ethics; Flow Cytometry; Formulation; Gene Expression Profile; Genomics; Human; Immune; Immune response; Immune system; Immunology; Immunology procedure; Immunophenotyping; In Vitro; Individual; Inflammatory; Influenza; Influenza vaccination; Lymphocyte; Maintenance; Measurement; Measures; Modality; Modeling; Molecular; Monitor; Multiple Sclerosis; Participant; Peptides; Peripheral Blood Mononuclear Cell; Population; Populations at Risk; Positioning Attribute; Role; Sampling; Seasonal Variations; Site; Specificity; Sphingosine-1-Phosphate Receptor; T cell response; T memory cell; T-Lymphocyte; Technology; Time; Tissues; Treatment Protocols; Vaccination; Vaccines; Viral; Virus; anti-CD20; antiviral immunity; cohort; cytokine; healthy volunteer; high dimensionality; immune imaging; immune modulating agents; in vivo; influenza virus vaccine; lymph nodes; multiple sclerosis patient; novel vaccines; radiological imaging; response; seasonal influenza; small molecule; vaccine response; vaccine trial

PROJECT 3: PROJECT SUMMARY Successful vaccination represents the interplay of multiple, interacting innate, humoral, and cellular adaptive factors which have not yet been fully defined. The immune system as a whole is engaged, including both tissue resident and circulating populations. While we have elucidated important elements of the integrated response, many nuances in the role of selected cell subtypes remain to be determined both in isolation and in combination. One approach to dissect complex networks of immune responses that has been applied successfully in model systems - and in vitro for human immunology – involves molecularly specific, targeted perturbation of the baseline network of cellular interactions. Subsequent changes in immune responses can then begin to highlight the elements of the network involved in vaccine response related to the molecular entity that was targeted. Here, we deploy this strategy leveraging the fact that individuals with multiple sclerosis (MS) are treated with molecularly specific treatments and therefore present an opportunity to examine, in vivo, how targeted perturbation alters established responses to CMV and response to new vaccines in humans. We focus on two such treatments which are used as monotherapy: (1) B cell depletion with ocrelizumab and (2) sequestration of lymphocytes in the lymph node using fingolimod. We propose to longitudinally sample participants with MS treated with one of these two therapies - and healthy subjects to serve as a reference – through three vaccination cycles: two with SARS-CoV-2 vaccine and one with an influenza vaccine. At the pre-vaccination time point and up to 8 subsequent time points, we will assess humoral and T cell responses to CMV, influenza and SARS-CoV-2 using multiple different modalities, including high-dimensional cytometric, single cell CITEseq, and functional assessments in response to antigen-specific stimulation. We will therefore be in a rare position to model longitudinal responses to multiple different, antigen-specific stimulations over 3-4 years in the healthy and in vivo targeted perturbation context.

项目 3：项目摘要 成功的疫苗接种代表了多种相互作用的先天性、体液性和细胞适应性的相互作用 尚未完全确定的因素。整个免疫系统都参与其中，包括两个组织 常住人口和流动人口。虽然我们已经阐明了综合应对措施的重要要素， 所选细胞亚型的作用的许多细微差别仍有待单独和组合确定。 一种剖析复杂免疫反应网络的方法已成功应用于模型中 系统 - 以及人类免疫学的体外 - 涉及分子特异性、有针对性的基线扰动 细胞相互作用网络。免疫反应的后续变化可以开始凸显 参与与目标分子实体相关的疫苗反应的网络元素。在这里，我们 部署这一策略是利用多发性硬化症 (MS) 患者接受分子治疗这一事实 特定的治疗，因此提供了一个机会来检查，在体内，有针对性的扰动如何改变 确定了人类对 CMV 的反应和对新疫苗的反应。我们重点关注两种这样的治疗方法 用作单一疗法：(1) 使用 ocrelizumab 消除 B 细胞，以及 (2) 隔离淋巴细胞 使用芬戈莫德淋巴结。我们建议对接受其中一种治疗的多发性硬化症参与者进行纵向抽样 这两种疗法——并以健康受试者作为参考——通过三个疫苗接种周期：两个周期 SARS-CoV-2 疫苗和一种流感疫苗。在疫苗接种前的时间点和最多 8 在随后的时间点，我们将使用以下方法评估体液和 T 细胞对 CMV、流感和 SARS-CoV-2 的反应： 多种不同的模式，包括高维细胞计数、单细胞 CITEseq 和功能 对抗原特异性刺激的反应评估。因此，我们将处于一个罕见的位置来建模 3-4年内健康人和体内对多种不同抗原特异性刺激的纵向反应 有针对性的扰动背景。