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.

项目摘要/摘要 流感病毒感染引起全球发病率和死亡率，并构成严重的大流行风险 病毒的缓解和突变倾向。当前的影响引起特定的应变特异性 响应，仅根据年份有效的10-60％。迫切需要普遍 流感疫苗会引起稳健，持久和广泛的交叉反应B和T细胞反应。设计 这样的疫苗将需要全面了解宿主和抗原的特征 调节影响力特异性响应的大小，质量和广度。大多数人类影响力研究 即使导致产物的关键细胞决策，也仅限于外周血采样 自适应免疫反应发生在淋巴组织中。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通路，引起保护性 人类的免疫反应。我们的中心假设是来自粘膜淋巴组织的免疫特征 在开发出强大的免疫策略中，比外周血比外周血更有意义 并广泛反应影响力反应。为了解决这个问题，我们建议利用高 吞吐物在体外器官平台衍生自原发性扁桃体组织。扁桃体都被认为是 淋巴组织和粘膜组织；他们也可以从接受其他健康的患者那里获得 扁桃体切除术或阻塞性睡眠呼吸暂停。参与者在人口统计学上多样化和掩护 整个人类年龄跨度；男性和女性的比例相似。免疫器官得出 从扁桃体中，准确地对人类生发中心反应，特定抗体分泌和T细胞激活进行建模 响应影响抗原。他们还能够捕获宿主介导的个体间免疫变化 与患者年龄，性别和免疫史有关。此外，可以使用扁桃体器官来跟踪动力学 自适应免疫反应，并实现合理设计通用所需的机械见解 影响力疫苗。该应用程序的目的是了解主机功能和影响力如何 有助于人类影响力的影响力的大小和质量。该提议是 在强大的初步数据的支持下，如果成功，将为普遍影响 通过识别保护和预测因素来开发疫苗。我们将结合全面 表型和机械实验方法来定义人淋巴组织中的关键驱动因素 这导致狭窄，特定于应变的反应。该应用的新颖性在于系统免疫学 将人口统计学，血清学，表型，功能和曲目读数整合到良好的方法 受控的免疫器官平台。拟议的实验的完成将有助于我们快速识别 保护和指导广泛交叉反应的普遍影响者疫苗的设计和测试。