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

基本信息

批准号：
10206139
负责人：
Heather Fahlenkamp
金额：
$ 51.79万
依托单位：
OKLAHOMA MEDICAL RESEARCH FOUNDATION
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-20 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206139
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 Patients Phenotype Physiological Play Population Predisposition 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 innate immune pathways lung basal segment macrophage monocyte neonate neutrophil novel novel therapeutics novel vaccines peripheral blood preventive intervention recruit response scaffold treatment strategy vaccine development

项目摘要

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) 是全世界病毒性细支气管炎和肺炎的主要原因，可感染超过70%的儿童在第一年。 RSV 导致婴儿更频繁、更严重的感染与成人相比。由于宿主免疫系统的存在，疫苗的开发变得更加复杂。对 RSV 的反应在疾病发病机制中发挥着重要作用。 RSV 发病机制的关键可能在于定义与免疫不成熟时期免疫反应缺陷相关的机制。由于以下原因，人类婴儿肺驻留髓细胞对 RSV 反应的研究受到限制：缺乏可用的模型。虽然可以测量气管中存在的细胞因子和趋化因子 RSV 细支气管炎患者的抽吸物，很难获得足够数量的细胞来进行机械分析可能阐明幼儿先天免疫途径缺陷的研究。因此，新需要有利于控制感染时间和细胞操作的模型来比较抗 RSV 新生儿和成人骨髓细胞的反应。了解这些机制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 人体组织工程肺模型 (3D-HTLM)，该模型表现出针对感染原的正常免疫反应，以阐明一些病毒和宿主决定因素。该项目的目标是创建一个 3D-HTLM，用于确定免疫不成熟导致 RSV 发病机制更严重。肺模型的一个优点是能够通过比较幼儿和儿童与成人的反应来测试免疫不成熟的影响免疫细胞抵抗 RSV 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、呼吸道上皮、支持基质细胞和骨髓细胞，包括常驻细胞和炎症细胞。 3D-HTLM 包括 3D 支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 内的肺部微环境是否指示肺驻留髓细胞的分化。目标 2：比较骨髓细胞的先天免疫反应从新生儿脐带血、幼儿和成人中分离出RSV感染的3D-HTLM。该项目将产生有关免疫反应的新信息，从而为预防提供新的目标 RSV感染的治疗和干预，组织工程肺模型也可用于测试 RSV 治疗策略。此外，扩大我们关于细胞如何相互作用的知识其他及其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。