Molecular Mechanisms Associated with Immune Maturation in Infants

描述(申请人提供)：在世界范围内，每年有多达200万婴儿在5岁之前死亡。疾病易感性和死亡率在婴儿出生后的头6个月最高。 然而，我们对出生后免疫发育及其与疾病易感性、婴儿死亡率和儿童疫苗效力的关系的了解仍然有限。大多数与婴儿免疫发育相关的免疫学数据都是基于脐带血和成人血的比较。很少进行纵向研究，因此免疫成熟的动力学在很大程度上是未知的。样本获取、样本数量和样本收集的频率存在明显的障碍，因此以前的许多研究仅限于低样本数量(50名婴儿)。在这项拟议的研究中，我们将获得560名婴儿的纵向样本。一个独特的方面将是纳入健康的早产儿。因此，我们将能够直接比较早产儿和足月儿的免疫发育情况。这些研究将为胎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效力提供新的见解。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。目前还缺乏明确婴儿免疫反应性降低的分子机制的研究。很少有研究试图定义与年龄相关的信号通路、基因表达或调控方面的差异，这些差异可能解释了观察到的婴儿和成人免疫细胞群体之间的功能差异。本研究的具体目的是研究髓系树突状细胞(MDC)和CD4+T细胞从出生到1岁的免疫成熟情况，并确定这两类细胞功能发育的分子机制。髓系树突状细胞和CD4+T细胞分别在先天免疫和获得性免疫中发挥核心作用。为了研究出生后免疫成熟的动力学，确定与免疫发育相关的分子机制，并确定早产儿和足月儿免疫发育的潜在差异，我们将追求三个特定的目标。在目标1和目标2中，我们将分别研究从出生到1岁的早产儿和足月儿的MDC和CD4+T细胞成熟情况。在最后一个目标中，我们将测试早产儿和足月儿在免疫发育方面的潜在差异如何反映在疫苗诱导的免疫中。这一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LAB)以及W.Price博士领导的新生儿和儿科医生共同努力的结果。

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.