Placental determinants of neonatal immune function in maternal HIV infection

摘要：感染艾滋病毒但未感染(HEU)的婴儿死亡的可能性是未感染艾滋病毒的婴儿的两倍 未感染婴儿(HUU)，主要来自其他传染病。我们迫切需要了解如何 母亲感染艾滋病毒--无论是否得到控制--都会影响新生儿免疫系统的发育。 有了这些信息，我们可以开发算法来预防高浓缩铀中的传染病，这可以解释他们的 功能性免疫缺陷。 我们假设，母体感染艾滋病毒会导致胎盘发炎，降低母体对母体的感染率 儿童抗体的转移，以及损害新生儿免疫系统的差异编程 对疫苗的免疫反应。为了验证这一假设，我们将结合临床数据和免疫学数据。 将从孕妇、胎盘和新生儿样本中获取，这些样本是NIH资助的R01项目的一部分 自2014年以来，我们一直在印度进行研究。我们招募了一群独特的、定义明确的母亲- HIV携带者和非HIV携带者的婴儿配对，在怀孕期间和第一年进行纵向跟踪 产后。我们建议利用这些储存的样本来实现以下目标： 目的1.比较母血、胎盘和脐带血样本中Treg/CD8+T细胞的比例 产妇的艾滋病毒状况和病毒载量。这一目标将建立免疫细胞和 用流式细胞仪、免疫卡技术检测母血、胎盘和脐带血样本中的细胞因子 免疫组织化学染色。了解母体和胎盘免疫学与新生儿的关系 免疫发育可以帮助我们预测哪些婴儿对病原体的免疫反应会减弱。 目的2.测定胎盘免疫功能对婴儿体液和细胞的影响 豁免权。这一目标将(1)确定HIV如何减少抗体通过胎盘转移到Key 导致HEU婴儿死亡的呼吸道病原体，包括肺炎链球菌、流感嗜血杆菌和流感 病毒；以及(2)确定胎盘炎症是否影响婴儿对 卡介苗。 利用这些数据，我们可以开发筛查测试来预测哪些新生儿的免疫力最强 出生时就妥协。研究胎盘在新生儿免疫系统发育中的作用可能 还揭示了HEU和HUU婴儿之间的关键差异，这将使我们能够优化对这些弱势群体的护理 人口。

ABSTRACT: HIV-exposed but uninfected (HEU) infants are twice as likely to die as HIV-unexposed and uninfected infants (HUU), mainly from other infectious diseases. There is an urgent need to understand how maternal HIV infection–whether controlled or not– impacts the development of the neonatal immune system. With this information, we can develop algorithms to prevent infectious diseases in HEU that account for their functional immune deficits. We hypothesize that maternal HIV infection results in inflammation of the placenta, decreased maternal-to- child transfer of antibodies, and differential programming of the neonatal immune system that impairs the immune response to vaccines. To test this hypothesis, we will integrate clinical data with immunologic data we will obtain from maternal, placenta and neonatal samples that were collected as part of an NIH-funded R01 study we have been conducting in India since 2014. We enrolled a unique, well-defined cohort of maternal- infant pairs with and without HIV and followed them longitudinally through pregnancy and the first year postpartum. We propose to capitalize on these stored samples to address the following aims: Aim 1. Compare the Treg/CD8+ T cell ratio in maternal blood, placenta, and cord blood samples by maternal HIV status and viral load. This aim will establish the relationship between immune cells and cytokines in maternal blood, placenta and cord blood samples, using flow cytometry, immunecard technology and immunohistochemical staining. Understanding how maternal and placental immunology relate to neonatal immune development may help us predict which infants will have impaired immune responses to pathogens. Aim 2. Determine the effect of placental immune function on infants’ humoral and cellular immunity. This aim will (1) identify how HIV decreases the transplacental transfer of antibodies to key respiratory pathogens involved in HEU infant mortality, including S. pneumoniae, H. influenzae, and influenza virus; and (2) determine if placental inflammation impacts the longevity of the infant’s immune response to BCG vaccine. Using these data, we can develop screening tests to predict which neonates will have the greatest immune compromise at birth. Studying the role of the placenta in the development of the neonatal immune system may also reveal key differences between HEU and HUU infants that will allow us to optimize care for this vulnerable population.