Early Life Stress and Immune Dysfunction in Post-Institutionalized Adolescents

 描述(由申请人提供)：在人类中，缺乏明确的证据表明，仅限于产前-婴儿期的压力对免疫系统有编程样的影响。此外，人类对儿童不良状况的免疫相关性的研究并没有特别关注参与免疫调节的T细胞表型，这可能会损害对感染的反应能力。文献中的这两个空白都非常重要，因为它们限制了我们理解早期生活应激(ELS)损害一生健康的机制的能力。这款R21通过在一群独特的年轻人(14至17岁)中进行复杂的免疫表型和功能免疫分析来解决这些漏洞，这些年轻人在婴儿时期(36个月)从俄罗斯/东欧的孤儿院/机构被收养到美国资源充足且总体稳定、生活压力低的家庭。因此，这些年轻人的早期生活压力(ELS)是有限的 到产前婴儿期。有两个目标。目的1：确定ELS对青少年免疫反应的影响。血液样本将从30名收容后(PI)和30名对照青少年中采集。复杂的多色免疫表型将被用来表征淋巴细胞亚群，单核细胞的反应将在体外用刺激剂进行探测，上清液中的细胞因子水平将用多细胞因子阵列来测定。完整的血细胞计数和C反应蛋白水平也将被测定。在检测中收集的唾液皮质醇将评估血液采样引起的一过性皮质醇升高是否有助于各组之间的免疫差异。目的2.描述ELS青少年不同易感性的因素，包括扭曲的激素生物节律和ELS的严重程度。该项目的第二阶段将扩大样本量，包括30个额外的PI(总数=60)，提供足够的多样性，以确定机构护理的严重性和持续时间的影响，以及失调的HPA昼夜节律的中介影响，以预测刺激培养中T细胞库和细胞反应的变化。这项工作具有非常重要的意义，因为通过将重点放在那些在婴儿期后经历护理彻底改善的年轻人身上，它将提供迄今为止最有力的证据，证明产前婴儿期规划对人类免疫系统的影响，并强调防止早期剥夺和忽视的重要性。它还通过描绘可能在成年后潜在的健康风险的特定免疫改变，对于改善有早期不良护理病史的个人的预防性护理具有潜在的意义。它是人类ELS的第一个研究，采用了这样一个复杂的免疫小组，并结合了促炎偏见和免疫能力所不可或缺的措施，这是非常有创新性的。这个R21项目将为ELS免疫研究的新途径奠定基础，该研究专注于童年经历的挥之不去的后遗症。

 DESCRIPTION (provided by applicant): There is a dearth of evidence in humans definitively showing that stress confined to the prenatal-infancy period has programming-like effects on the immune system. In addition, human studies of immune correlates of adverse childhood conditions have not focused specifically T-cell phenotypes involved in immune regulation that may compromise the ability to respond to infection. Both of these gaps in the literature are highly significant in that they limit our ability to understand the mechanisms through which early life stress (ELS) impairs health across the life span. This R21 addresses these lacunae by conducting sophisticated immunophenotyping and functional immune assays in a unique population of youth (14 through 17 years of age) who as infants (< 36 months) were adopted from orphanages/institutions in Russia/Eastern Europe into well-resourced and generally stable, low-life-stress families in the US. The early life stress (ELS) for these youth, thus, was confined to the prenatal-infancy period. There are two aims. Aim 1: Determine the impact of ELS on immune responses of these youth now that they are adolescents. Blood samples will be obtained from 30 post-institutionalized (PI) and 30 comparison adolescents. Sophisticated multi-color immunophenotyping will be used to characterize lymphocyte subsets and mononuclear cell responses will be probed in vitro with stimulants, and cytokine levels in supernatants determined with multi-cytokine arrays. Complete blood counts and C-reactive protein levels also will be determined. Saliva cortisol collected at testing will assess whether transient cortisol elevations in response to blood sampling contribute to the immune differences between groups. Aim 2. Delineate factors that account for differential vulnerability among ELS youth, including distorted hormone biorhythms and severity of the ELS. The second phase of this project will expand the sample size to include 30 additional PI's (total=60), providing sufficient diversity to determine the influence of the severity and duration of institutional care and the mediating influence of dysregulated HPA diurnal rhythms to predict variation in the T cell repertoire and cellular responses in stimulated cultures. This work is highly significant because, by focusing on youth who experience radical improvements in care post-infancy, it will provide the strongest evidence to date of prenatal-infancy programming-like effects on the human immune system and underscores the importance of preventing early deprivation and neglect. It also has potential significance for improving the preventive care of individuals with a history of early adverse care, by delineating specific immune alterations that may underlie potential health risks later in adulthood. It is highly innovative in being the first study of ELS in humans to employ such a sophisticated immune panel and to combine measures that are integral to a pro-inflammatory bias and immune competence. This R21 project will lay the groundwork for a new avenue of ELS-immune research that is focused on lingering sequelae of childhood experiences.