Molecular Mechanisms Associated with Immune Maturation in Infants

与婴儿免疫成熟相关的分子机制

• 批准号: 8708750
• 负责人: Kristina De Paris
• 金额: $ 40.85万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8708750
• 关键词: 1 year old; Accounting; Adult; Affect; Age; Age-Months; Antibody Formation; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Birth; Blood; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Maturation; Cells; Childhood; Communicable Diseases; Data; Dendritic Cells; Development; Disease Outcome; Disease susceptibility; Frequencies; Gene Expression; Gene Expression Regulation; Gestational Age; Goals; Immune; Immune response; Immune system; Immunologics; Immunosuppressive Agents; Infant; Infant Mortality; Interferons; Kinetics; Knowledge; Life; Longitudinal Studies; Mediating; Molecular; Morbidity - disease rate; Myelogenous; Natural Immunity; Nature; Newborn Infant; Play; Population; Price; Research Personnel; Role; Sampling; Signal Transduction; Signaling Pathway Gene; Stimulus; Systems Development; T-Cell Development; T-Lymphocyte; Testing; Tetanus Helper Peptide; Translating; Umbilical Cord Blood; Vaccines; Vulnerable Populations; adaptive immunity; age related; base; clinically relevant; comparative; improved; in utero; infant morbidity/mortality; insight; mortality; neonate; novel; pathogen; pediatrician; public health relevance; response; sample collection; vaccine efficacy; vaccine-induced immunity

DESCRIPTION (provided by applicant): Worldwide, up to 2 million infants die each year before the age of 5. Disease susceptibility and mortality are highest in the first 6 months of age. However, our knowledge of immune development after birth and how it relates to disease susceptibility, infant mortality, and childhood vaccine efficacy is still limited. The majority of immunological data related to immune development in infants are based on the comparison of cord blood to adult blood. Few longitudinal studies have been performed, and thus the kinetics of immune maturation is largely unknown. Sample access, sample volumes and the frequencies at which sample collection is possible present obvious hurdles, and as a result many previous studies were limited to low sample numbers (<50 infants). In the proposed studies here, we will have access to longitudinal samples from 560 infants. A unique aspect will be the inclusion of healthy pre-term babies. Thus, we will be able to directly compare immune development between pre-term and full-term infants. These studies will provide new insights into how gestational age and immune maturation affect disease susceptibility, infant mortality and childhood vaccine efficacy. The long-term goal of our studies is to delineate distinct immune mechanisms that differ between infants and adults. There is a significant lack of studies defining the molecular mechanisms responsible for reduced immunologic responsiveness in infants. Few studies have attempted to define age-related differences in signaling pathways, gene expression or regulation that may account for the observed functional differences between infant and adult immune cell populations. The specific objective of the studies proposed here is to characterize the immune maturation of myeloid dendritic cells (mDC) and CD4+T cells from birth to 1 year of age and to define the molecular mechanisms involved in the functional development of these two cell populations. Myeloid DC and CD4+T cells play central roles in innate and adaptive immunity, respectively. To study the kinetics of immune maturation after birth, to define molecular mechanisms associated with immune development, and to determine potential differences in immune development in pre-and full-term infants, we will pursue 3 Specific Aims. In Aims 1 and 2, we will characterize mDC and CD4+T cell maturation, respectively, in pre-and full-term infants from birth to 1 year of age. In the last aim, we will tet how potential differences in immune development between pre- and full-term infants are reflected in vaccine-induced immunity. This knowledge should be of great clinical relevance, and demonstrates the translational nature of the proposed studies. The study is a collaborative effort by basic researchers (Dr. Abel and lab) and neonatologists and pediatricians led by Dr. W. Price.

描述（由申请人提供）：全球，每年5岁之前死亡200万婴儿。疾病的敏感性和死亡率在头6个月中最高。 但是，我们对出生后免疫发育的了解及其与疾病的易感性，婴儿死亡率和儿童疫苗功效的关系仍然有限。与婴儿免疫发育有关的大多数免疫数据是基于脐带血与成人血液的比较。很少进行纵向研究，因此免疫成熟的动力学在很大程度上尚不清楚。样品访问，样品量和可能采取样品收集的频率存在明显的障碍，因此许多先前的研究仅限于样本数量低（<50个婴儿）。在此处提出的研究中，我们将可以使用来自560名婴儿的纵向样本。一个独特的方面将是包括健康的前婴儿。因此，我们将能够直接比较前期婴儿和完整婴儿之间的免疫发育。这些研究将提供有关妊娠年龄和免疫成熟如何影响疾病易感性，婴儿死亡率和儿童疫苗功效的新见解。我们研究的长期目标是描述婴儿和成人之间不同的不同免疫机制。有很大的研究缺乏定义导致婴儿免疫反应降低的分子机制。很少有研究试图定义与年龄相关的信号通路，基因表达或调节的差异，这些差异可能解释了婴儿和成人免疫细胞种群之间观察到的功能差异。此处提出的研究的具体目标是表征从出生到1岁的髓样树突状细胞（MDC）和CD4+T细胞的免疫成熟，并定义参与这两个细胞群体功能发育所涉及的分子机制。髓样DC和CD4+T细胞分别在先天和适应性免疫中起着核心作用。为了研究出生后免疫成熟的动力学，以定义与免疫发育相关的分子机制，并确定完整前婴儿的免疫发育的潜在差异，我们将追求3个具体目标。在AIMS 1和2中，我们将分别表征MDC和CD4+T细胞的成熟，从出生到1岁。在最后一个目标中，我们将如何在疫苗诱导的免疫力中反映在前婴儿和完整婴儿之间的免疫发育中的潜在差异。这些知识应该具有很大的临床相关性，并证明了拟议研究的翻译性质。这项研究是基础研究人员（Abel博士和实验室）的合作努力，以及W. Price博士领导的新生儿学家和儿科医生。