A 3D human tissue-engineered lung model to study immune responses to Respiratory Syncytial Virus

用于研究呼吸道合胞病毒免疫反应的 3D 人体组织工程肺模型

• 批准号: 9789274
• 负责人: Heather Fahlenkamp
• 金额: $ 52.79万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-20 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789274
• 关键词: 3-Dimensional; Activities of Daily Living; Adopted; Adult; Age; Alveolar Macrophages; Animal Model; Antiviral Response; Aspirate substance; Biological Models; Biomedical Engineering; Blood; Bronchiolitis; Bronchoalveolar Lavage; Cell Communication; Cell surface; Cells; Child; Clinical Data; Communication; Dendritic Cells; Development; Disease; Distal; Endothelium; Engineering; Environment; Epithelial Cells; Exhibits; Experimental Models; Extracellular Matrix; Future; Goals; Homeostasis; Human; Immune; Immune response; Immunity; Immunologics; Infant; Infection; Infectious Agent; Inflammatory; Inflammatory Response; Influenza A virus; Innate Immune Response; Integration Host Factors; Knowledge; Life; Lung; Lung Transplantation; Lung diseases; Measures; Modeling; Morphology; Mus; Myeloid Cells; Neonatal; Newborn Infant; Outcomes Research; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Physiological; Play; Population; Predisposition; Preventive Intervention; Primary Infection; Production; Research; Research Project Grants; Respiratory Syncytial Virus Infections; Respiratory Syncytial Virus Vaccines; Respiratory syncytial virus; Role; Source; Stimulus; Stromal Cells; Structure of respiratory epithelium; Testing; Therapeutic Intervention; Time; Tissue Engineering; Umbilical Cord Blood; Vascular Endothelium; Viral; Viral Bronchiolitis; Viral Pathogenesis; Viral Pneumonia; Virulence Factors; Virus Diseases; Work; airway epithelium; cell motility; cell type; chemokine; cytokine; design; experience; human tissue; improved; lung basal segment; macrophage; monocyte; neonate; neutrophil; novel; novel therapeutics; novel vaccines; peripheral blood; recruit; response; scaffold; treatment strategy; vaccine development

Respiratory syncytial virus (RSV) is the leading cause of viral bronchiolitis and pneumonia worldwide, infecting more than 70% of children in the first year. RSV causes more frequent and severe infections in infants compared to adults. The development of vaccines has been complicated by the fact that host immune responses to RSV play a significant role in disease pathogenesis. A key to RSV pathogenesis may lie in defining the mechanisms associated with a deficient immune response at a time of immunological immaturity. The study of the responses of lung-resident myeloid cells to RSV in human infants has been limited due to the lack of available models. While it is possible to measure cytokines and chemokines present in tracheal aspirates in RSV bronchiolitis patients, it is difficult to obtain sufficient numbers of cells to perform mechanistic studies that might elucidate innate immune pathways that are defective in young children. Therefore, new models facilitating control of the timing of infection and cell manipulation are needed to compare the anti-RSV responses of neonatal and adult myeloid cells. An understanding of these mechanisms can aid in the design of new vaccines and therapies. Our long-term research goal is to use a 3D Human Tissue-Engineered Lung Model (3D-HTLM) that exhibits a normal immunological response against infectious agents to elucidate some of the viral and host determinants. The objective of this project is to create a 3D-HTLM that will be used to determine the mechanisms by which immunological immaturity leads to greater RSV pathogenesis. An advantage of the lung model is the ability to test the effect of immunological immaturity by comparing the response of young infants and children vs. adult immune cells to RSV infection. To achieve this goal, the 3D-HTLM will contain the cell types relevant to infection and an inflammatory response, including vascular endothelium, a respiratory epithelium, supporting stromal cells, and myeloid cells, both resident and inflammatory. The 3D-HTLM includes a 3D scaffold and extracellular matrix materials to allow for the correct cell physiological function and cell-to-cell interactions. We will pursue two specific aims. Aim 1: Determine if the lung microenvironment within the 3D-HTLM instructs the differentiation of lung resident myeloid cells. Aim 2: Compare the innate immune response of myeloid cells isolated from neonatal cord blood, young children and adults to RSV infection in the 3D-HTLM. The project will yield new information about the immune response that will provide new targets for preventative and therapeutic interventions of RSV infection, and the tissue-engineered lung model also may be used for testing RSV treatment strategies. In addition, expanding our knowledge about how cells interact with each other and with their environment will vertically advance the field of tissue engineering and the future development of an engineered lung for lung transplantation to treat a variety of lung diseases.

呼吸道合胞病毒(RSV)是世界范围内病毒性毛细支气管炎和肺炎的主要原因，感染 超过70%的儿童在第一年。呼吸道合胞病毒导致婴儿更频繁和更严重的感染 与成年人相比。由于宿主免疫的事实，疫苗的开发变得复杂 对RSV的应答在疾病的发病机制中起着重要作用。RSV致病的一个关键可能在于 确定与免疫不成熟时免疫反应不足有关的机制。 人肺髓系细胞对呼吸道合胞病毒的反应的研究一直受到限制。 缺少可用的型号。虽然可以测量气管中存在的细胞因子和趋化因子 在呼吸道合胞病毒毛细支气管炎患者中，很难获得足够数量的细胞来执行机械操作 可能阐明幼儿先天免疫途径缺陷的研究。因此，新的 需要便于控制感染时间和细胞操作的模型来比较抗RSV 新生儿和成人髓系细胞的反应。对这些机制的了解有助于设计 新的疫苗和疗法。 我们的长期研究目标是使用3D人类组织工程肺模型(3D-HTLM)，该模型展示了 针对感染性病原体的正常免疫反应，以阐明一些病毒和宿主的决定因素。 这个项目的目标是创建一个3D-HTLM，它将被用于确定 免疫不成熟导致更严重的RSV致病。肺模型的一个优点是能够 通过比较婴幼儿和儿童与成人的反应来检验免疫不成熟的影响 免疫细胞抵抗呼吸道合胞病毒感染。为了实现这一目标，3D-HTLM将包含与 感染和炎症反应，包括血管内皮细胞，呼吸道上皮，支持 基质细胞和髓样细胞，既有常驻的，也有炎症的。3D-HTLM包括3D脚手架和 细胞外基质材料，以实现正确的细胞生理功能和细胞间的相互作用。 我们将追求两个具体目标。目标1：确定3D-HTLM内的肺微环境是否指示 肺内常驻髓系细胞的分化。目的2：比较髓系细胞的天然免疫反应 从新生儿脐带血、婴幼儿和成人分离到呼吸道合胞病毒感染的3D-HTLM。 该项目将提供有关免疫反应的新信息，为预防提供新的靶点。 和RSV感染的治疗干预，以及组织工程肺模型也可以用于 测试呼吸道合胞病毒的治疗策略。此外，扩展我们对细胞如何相互作用的知识 其他和他们的环境将垂直推进组织工程领域和未来 开发用于肺移植的工程肺以治疗多种肺部疾病。