Molecular Mechanisms Associated with Immune Maturation in Infants

描述（由申请人提供）：全世界每年有多达200万婴儿在5岁之前死亡。疾病易感性和死亡率在前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有效性的关系的认识仍然有限。大多数与婴儿免疫发育相关的免疫学数据是基于脐带血与成人血液的比较。很少有纵向研究已经进行，因此免疫成熟的动力学在很大程度上是未知的。样本获取、样本量和样本采集频率存在明显障碍，因此，许多先前的研究仅限于少量样本（<50名婴儿）。在这里的拟议研究中，我们将获得来自560名婴儿的纵向样本。一个独特的方面将是包括健康的早产儿。因此，我们将能够直接比较早产儿和足月儿之间的免疫发育。这些研究将为孕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免疫机制。有一个显着缺乏研究定义的分子机制，负责降低婴儿的免疫反应。很少有研究试图定义与年龄相关的信号通路、基因表达或调控差异，这些差异可能是婴儿和成人免疫细胞群之间观察到的功能差异的原因。本文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，并确定参与这两种细胞群功能发育的分子机制。髓样DC和CD4+T细胞分别在先天性和适应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3个特定目标。在目标1和2中，我们将分别描述从出生到1岁的早产儿和足月儿中的mDC和CD4+T细胞成熟。在最后一个目标中，我们将泰特早产儿和足月儿之间免疫发育的潜在差异如何反映在疫苗诱导的免疫中。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转化性质。这项研究是由基础研究人员（Abel博士和实验室）以及W。价格

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.