Peripheral Immune Development in Premature Infants with and without NEC

患有和不患有 NEC 的早产儿的周围免疫发育

• 批准号: 10038410
• 负责人: Liza Konnikova
• 金额: $ 22.33万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-05 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10038410
• 关键词: Abnormal Cell; Address; Age; Age-Months; Birth; Blood; Blood Volume; Cell Lineage; Cells; Cessation of life; Complex; Complication; Cytometry; Data; Development; Disease; Economic Burden; Etiology; Eye; Fetus; Foundations; Functional disorder; Gestational Age; Goals; High Prevalence; Human; Immune; Immune system; Immunity; Immunological Models; Immunophenotyping; Incidence; Infant; Inflammation; Inflammatory; Intestines; Lead; Life; Maps; Mediating; Metadata; Methodology; Methods; Morbidity - disease rate; Mucosal Immune System; Mus; Natural Immunity; Nature; Necrotizing Enterocolitis; Neonatal; Pathogenesis; Patients; Perinatal; Peripheral; Peripheral Blood Mononuclear Cell; Phenotype; Population; Predisposition; Premature Birth; Premature Infant; Prevention; Prevention strategy; Regulatory Pathway; Research; Sampling; Second Pregnancy Trimester; Secondary to; Small Intestines; Solid; T memory cell; T-Lymphocyte; Time; Tissues; United States; Very Low Birth Weight Infant; Work; adaptive immunity; cell type; cost estimate; fetal; improved; interest; machine learning algorithm; macrophage; monocyte; mortality; peripheral blood; premature; prevent; specific biomarkers; therapy development

Title: Peripheral Immune Development in Premature Infants with and without NEC Abstract: Necrotizing enterocolitis (NEC) is a devastating complication of prematurity that frequently results in death (20- 50%) or severe systemic complications. Although NEC is a multifactorial disease, its precise etiology continues to be poorly understood. As such, there are still no effective prevention methods or treatments available. Given increased intestinal and systemic inflammation seen in NEC, it is likely that the dysregulation of the immune system contributes to its pathogenesis. In order to better understand NEC pathogenesis, it is essential to have a solid understanding of normal immune development that occurs over the first two months of age in premature infants. Our preliminary data obtained from fetuses, patients with NEC and control subjects, show that there is a drastic reduction of total and tissue resident memory T cells in the intestinal tissue and an increase in T cells in the periphery. Moreover, NEC is associated with a significant increase in pro-inflammatory macrophages in intestinal tissue, and a concomitant decrease in circulating monocytes. Recent work has begun to address how neonatal peripheral immunity develops. However, data on the peripheral immune development in premature infants over the first two months of life is sparse. Therefore, the goal of this exploratory proposal is to define normal immune development of premature infants over the first two months of life and characterize its dysregulation in patients with NEC. The overarching hypothesis of this proposal is that development of the peripheral immune system in preterm infants is different in the innate and adaptive immune compartments from that of term infants, and it is this difference that makes them susceptible to NEC. As the blood volume in premature infants is limited, we have developed a methodology to perform deep immunophenotyping on as little as 100 µliters of blood using mass cytometry time of flight (CyTOF). This unique methodology will allow us to address the hypothesis, with the following aims: 1) Define the peripheral immune development of premature infants (<32 weeks) over the first two months of life. We will perform CyTOF on peripheral blood from 50 premature infants, with samples collected at 0, 1, 2, 4, and 8 weeks. Deep characterization of the immune cell landscape and maps of the developmental trajectories of the major cell lineages in premature infants will be generated. 2) Identify peripheral immune cell abnormalities associated with the development of NEC. We will identify dysregulation of immune population trajectories specific to premature infants who develop NEC. This information will provide us with a model for the immune cell mechanism underlying susceptibility to NEC. This project would represent the first detailed deep examination of the development of the immune system in premature infants with and without NEC over the first two months, and will provide sufficient data for the development of a large-scale, in-depth study of the mechanism underlying the development of NEC.

标题： 有或没有NEC的早产婴儿的外周免疫发育 抽象的： 坏死性小肠结肠炎（NEC）是毁灭性的早产并发症，经常导致死亡（20- 50％）或严重的全身并发症。尽管NEC是一种多因素疾病，但其精确的病因仍在继续 理解不足。因此，仍然没有有效的预防方法或治疗方法。给出 NEC中看到的肠道和全身性炎症增加，免疫失调可能 系统有助于其发病机理。为了更好地了解NEC发病机理，必须 对正常免疫发育的扎实理解，该免疫发育在早年的前两个月发生 婴儿。我们从胎儿，NEC和对照受试者的患者获得的初步数据表明，有一个 肠道组织中总和居民记忆T细胞的大幅度降低，T细胞中T细胞的增加 外围。此外，NEC与促炎性巨噬细胞的显着增加有关 肠组织，循环单核细胞的伴随降低。最近的工作已经开始解决如何 新生儿外周免疫学发展。但是，关于早产外周免疫发展的数据 生命的前两个月的婴儿很少。因此，该探索性建议的目的是定义 在生命的头两个月中，过早婴儿的正常免疫发育，并表征 NEC患者的失调。该提议的总体假设是 早产儿中的外围免疫系统在先天和适应性免疫固定中有所不同 来自术语婴儿的隔间，正是这种差异使他们容易受到NEC的影响。作为 早产婴儿的血量有限，我们已经开发了一种方法来进行深度 使用质量细胞仪（CYTOF）进行的低至100 µLiter的血液升级的免疫表型。这个独特 方法学将使我们能够解决以下目的：1）定义周围免疫 在生命的头两个月中，早产儿（<32周）的发展。我们将在 来自50位早产儿的外周血，在0、1、2、4和8周收集样品。深的 免疫细胞景观的表征和主要细胞发育轨迹的地图 将产生早产婴儿的谱系。 2）识别外周免疫鼠标异常 随着NEC的发展。我们将确定特定于 发展NEC的早产婴儿。这些信息将为我们提供免疫细胞的模型 对NEC敏感的机制。该项目将代表对 头两个月内有或没有NEC的早产儿中免疫系统的发展， 并将提供足够的数据，以开发对基本机制的大规模，深入研究 NEC的发展。