Investigating protective adaptive immune responses to influenza antigens using human tonsil organoids

使用人扁桃体类器官研究对流感抗原的保护性适应性免疫反应

• 批准号: 10733719
• 负责人: Lisa Wagar
• 金额: $ 64.26万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10733719
• 关键词: Address; Adjuvant; Affect; Age; Antibodies; Antibody Affinity; Antibody Diversity; Antibody Response; Antigens; Area; B-Lymphocytes; Blood; Blood specimen; CD4 Positive T Lymphocytes; Cell Communication; Cell Differentiation process; Cell Maintenance; Cells; Childhood; Clinical; Data; Disparate; Emerging Communicable Diseases; Female; Frequencies; Future; Goals; Helper-Inducer T-Lymphocyte; Human; Hypertrophy; Immune; Immune response; Immunity; Immunology; In Vitro; Individual; Infection; Influenza; Integration Host Factors; Investigation; Kinetics; Knowledge; Life; Lymphoid Tissue; Mediating; Medicine; Modality; Molecular; Morbidity - disease rate; Mucous Membrane; Mutation; Nature; Obstructive Sleep Apnea; Organoids; Participant; Patients; Phenotype; Plasma; Population; Productivity; Protein Array; Recording of previous events; Research; Role; Seasons; Serology; Signal Pathway; Signal Transduction; Structure of germinal center of lymph node; System; T cell response; T-Cell Activation; T-Lymphocyte; Technology; Testing; Thromboplastin; Tissues; Tonsil; Tonsillectomy; Vaccination; Vaccine Design; Vaccines; Variant; Virus; adaptive immune response; adaptive immunity; age related; antibody detection; cross reactivity; design; early childhood; experimental study; human model; in vivo; in vivo evaluation; influenza infection; influenza virus strain; influenza virus vaccine; insight; male; mortality; neutralizing antibody; new technology; novel; novel vaccines; pandemic potential; peripheral blood; rational design; recruit; response; sex; universal influenza vaccine; vaccination strategy; vaccine development; vaccine trial

PROJECT SUMMARY/ABSTRACT Influenza virus infections cause significant global morbidity and mortality and pose a serious pandemic risk due to the virus’s propensity for reassortment and mutation. Current influenza vaccines elicit strain-specific responses and are only 10-60% effective depending on the year. There is an urgent need for a universal influenza vaccine that elicits robust, persistent, and broadly cross-reactive B and T cell responses. Designing such a vaccine will require a comprehensive understanding of how features from both the host and the antigen modulate the magnitude, quality, and breadth of the influenza-specific response. Most human influenza studies have been limited to peripheral blood sampling, even though the critical cellular decisions that lead to productive adaptive immune responses occur within lymphoid tissues. Our long-term goal is to define the dynamics of the lymphoid tissue microenvironment, including cell-cell interactions and signaling pathways, that elicit protective immune responses in humans. Our central hypothesis is that immune signatures from mucosal lymphoid tissue are significantly more informative than peripheral blood in developing immunization strategies that elicit robust and broadly cross-reactive influenza responses. To address this question, we propose to leverage a high throughput in vitro organoid platform derived from primary human tonsil tissues. Tonsils are considered both lymphoid and mucosal tissues; they are also accessible from otherwise-healthy patients undergoing tonsillectomy for hypertrophy or obstructive sleep apnea. Participants are demographically diverse and cover the full human age span; males and females are represented at similar proportions. Immune organoids derived from tonsils accurately model human germinal center responses, specific antibody secretion, and T cell activation in response to influenza antigens. They are also able to capture host-mediated inter-individual immune variation related to patient age, sex, and immune history. Furthermore, tonsil organoids can be used to track the kinetics of the adaptive immune response and enable the mechanistic insights needed to rationally design a universal influenza vaccine. The goal of this application is to understand how host features and influenza antigen features contribute to both the magnitude and quality of the influenza immune response in humans. This proposal is supported by strong preliminary data and if successful, will open new areas of investigation for universal influenza vaccine development by identifying correlates and predictors of protection. We will combine comprehensive phenotyping and mechanistic experimental approaches to define the key drivers within human lymphoid tissues that lead to narrow, strain-specific responses. The novelty of this application lies in the systems immunology approach that integrates demographic, serological, phenotypic, functional, and repertoire readouts in a well- controlled immune organoid platform. Completion of the proposed experiments will help us rapidly identify correlates of protection and guide the design and testing of a broadly cross-reactive universal influenza vaccine.

项目总结/摘要 流感病毒感染导致全球显著的发病率和死亡率，并构成严重的大流行风险， 病毒的重组和突变倾向目前的流感疫苗引起菌株特异性 反应和只有10-60%的有效性取决于一年。迫切需要一个普遍的 流感疫苗激发了稳健、持久和广泛交叉反应性B和T细胞应答。设计 这样的疫苗需要全面了解宿主和抗原的特性 调节流感特异性反应的幅度、质量和广度。大多数人类流感研究 一直局限于外周血采样，即使关键的细胞决定，导致生产 适应性免疫应答发生在淋巴组织内。我们的长期目标是定义 淋巴组织微环境，包括细胞-细胞相互作用和信号传导途径， 人类的免疫反应。我们的中心假设是粘膜淋巴组织的免疫信号 在制定免疫策略方面， 和广泛交叉反应的流感反应。为了解决这个问题，我们建议利用一个高 来源于原代人扁桃体组织的体外类器官平台的通量。扁桃体被认为是 淋巴和粘膜组织;它们也可以从其他健康的患者接受 扁桃体切除术治疗肥大或阻塞性睡眠呼吸暂停。参与者在人口统计学上是多样化的， 人类的整个年龄段;男性和女性的比例相似。免疫类器官衍生 从扁桃体中精确模拟人类生殖中心反应、特异性抗体分泌和T细胞活化 对流感抗原的反应。它们还能够捕获宿主介导的个体间免疫变异 与患者年龄、性别和免疫史有关。此外，扁桃体类器官可用于跟踪动力学 适应性免疫反应，并使合理设计一个通用的 流感疫苗。本应用程序的目标是了解宿主特征和流感抗原特征 有助于人类流感免疫应答的程度和质量。这项建议是 如果成功的话，将为普遍性流感开辟新的研究领域。 通过识别保护的相关因素和预测因素来开发疫苗。我们将联合收割机 确定人类淋巴组织内关键驱动因素的表型和机制实验方法 这导致了狭窄的、菌株特异性的反应。这种应用的新奇在于系统免疫学 一种将人口统计学、血清学、表型、功能和库读数整合在一起的方法， 受控免疫类器官平台。完成拟议的实验将有助于我们迅速确定 保护的相关性，并指导广泛交叉反应的通用流感疫苗的设计和测试。