Layering of the human immune system, viral infections, and childhood asthma

人体免疫系统的分层、病毒感染和儿童哮喘

基本信息

批准号：
8689898
负责人：
JOSEPH M MCCUNE
金额：
$ 37.6万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-21 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8689898
关键词：
Address Admixture Adult Anatomy Appearance Area Asthma Basophils Birds Birth Blood specimen Breathing CD4 Positive T Lymphocytes Cell Lineage Cells Child Childhood Childhood Asthma Chronic Dendritic Cells Development Diagnosis Disease Effector Cell Environment Environmental Risk Factor Equilibrium Event Fetus Functional disorder Gene Expression Generations Genetic Growth Helper-Inducer T-Lymphocyte Hematopoiesis Hematopoietic Human IgE Immune Immune response Immune system Individual Infectious Agent Inflammation Interleukin-13 Interleukin-4 Interleukin-5 Lead Life Literature Location Maintenance Mediating Mothers Mus Myeloid Cells Nature Neonatal Newborn Infant Pathway interactions Phenotype Physiological Predisposition Pregnancy Property Recurrence Regulatory T-Lymphocyte Reporting Respiratory Tract Infections Respiratory physiology Staging Stem cells Structure of parenchyma of lung System T-Lymphocyte Time Tissues Umbilical Cord Blood Variant Viral Virus Virus Diseases Wheezing airway epithelium airway hyperresponsiveness early childhood fetal in utero insight lymph nodes mast cell migration neonate novel public health relevance research study respiratory response stem

项目摘要

DESCRIPTION (provided by applicant): The susceptibility of newborns to recurrent episodes of virus-induced wheezing and atopic disorders (such as asthma) has been associated with a combination of genetic and environmental factors that favor the generation of T helper 2 (Th2) cells over T helper 1 (Th1) cells. In ongoing experiments, we have discovered a governing feature of human immune system ontogeny that explains Th2 dominance in utero and that may also determine the propensity of some but not all neonates to preferentially sustain Th2-type responses after birth. Thus, the fetal immune system is derived from multi-lineage hematopoietic stem/progenitor cells (HSPCs) that give rise to tolerogenic regulatory T cells while the adult immune system is derived from distinct HSPCs that are more likely to give rise to immunoreactive T effector cells. We hypothesize that different neonates may have varying proportions of these two compartments and that those with a higher proportion of the fetal compartment may be more predisposed to sustaining Th2 responses for a longer period of time after birth. This hypothesis will be addressed in experiments of the following Specific Aims: (1) to confirm and extend previous findings that there are gene expression and functional differences that distinguish fetal and adult myeloid cells; (2) to determine whether there is inter individual variation in the admixture of fetal and adult T and/or myeloid cells in normal umbilical cord blood (UCB) samples; and (3) to determine whether skewed fetal-to-adult T and/or myeloid cell ratios in UCB are predictive of the development of viral respiratory illness and atopic disorders, e.g. asthma. These experiments should lead to a better understanding of the pathophysiology of viral respiratory illnesses and atopic disorders of childhood, and may also generate novel insights important for the diagnosis and treatment of such diseases. PUBLIC HEALTH RELEVANCE: Two hematopoietic stem/progenitor cells have been detected in the context of human ontogeny, one that gives rise to tolerogenic T cells in utero and another that gives rise to immunoreactive T cells after birth. The studies of this proposal address the possibility that sequential "layering" of fetal-type and adult-type T cells and myeloid cells may occur, that different children may be born with varying admixtures of the two, and that such variability may underlie susceptibility to viral respiratory infections and asthma after birth.

描述（由申请人提供）：新生儿对病毒引起的喘息和特应性疾病的复发性发作的敏感性（例如哮喘）与遗传和环境因素的组合有关，这些因素有利于T Helper 2（TH2）细胞在T Helper 1（TH1）细胞上产生T Helper 2（Th2）细胞。在正在进行的实验中，我们发现了人类免疫系统个体发育的管理特征，该特征解释了子宫内的Th2优势，这也可能决定了某些但不是所有新生儿在出生后优先维持Th2型反应的倾向。因此，胎儿免疫系统源自多乳腺造血干/祖细胞（HSPC），这些造血系统会引起耐受性调节性T细胞，而成年免疫系统则来自不同的HSPC，这些HSPC更可能引起免疫反应性T型T效应细胞。我们假设不同的新生儿可能在这两个隔间中具有不同的比例，并且那些胎儿区室比例较高的隔室的比例可能更容易倾向于在出生后更长的时间内维持TH2反应。该假设将在以下特定目的的实验中解决：（1）确认并扩展了先前的发现，即有区别胎儿和成年髓样细胞的基因表达和功能差异；（2）确定是否存在正常脐带中胎儿和成人T和/或髓样细胞混合的个体变化脐带血（UCB）样品；（3）确定UCB中偏斜的胎儿与/或髓样细胞比是否可以预测病毒呼吸道疾病和特应性疾病的发展，例如哮喘。这些实验应该可以更好地了解病毒呼吸道疾病的病理生理学和儿童特征性疾病，并且还可能产生对诊断和治疗此类疾病重要的新颖见解。公共卫生相关性：在人体个体发育中检测到了两个造血干/祖细胞，一种会引起子宫内的耐受性T细胞，另一个引起出生后的免疫反应性T细胞。该提案的研究涉及可能发生胎儿型和成人型T细胞和髓样细胞的顺序“分层”的可能性，可能会出现两者中不同的儿童出生的不同儿童，并且这种可变性可能是对病毒呼吸道感染和出生后病毒呼吸道感染和哮喘的敏感性的基础。