Antigen exposure in utero: impacts on newborn immunity and infectious diseases

子宫内抗原暴露：对新生儿免疫力和传染病的影响

• 批准号: 8991705
• 负责人: Cristiana Cairo
• 金额: $ 37.26万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8991705
• 关键词: Address; Adult; Affect; Africa South of the Sahara; African; Age-Years; Antigens; Attenuated; Bacteria; Birth; Blood; Blood Circulation; Blood specimen; Calmette-Guerin Bacillus; Cause of Death; Cell Maturation; Cell physiology; Cells; Child; Childhood; Chronic; Clinical; Clinical Trials; Collaborations; Communicable Diseases; Contracts; Country; Dendritic Cells; Enrollment; Erythrocytes; Exposure to; Functional disorder; Genus Mycobacterium; Goals; Haplotypes; Health; Homeostasis; Immune; Immune response; Immune system; Immunity; Individual; Infant; Infection; Infectious Agent; Inflammation; Interferon Type II; Intervention; Link; Logistics; Lymphocyte; Malaria; Malawi; Maternal-Fetal Exchange; Measures; Morbidity - disease rate; Mothers; Mycobacterium tuberculosis; Natural Immunity; Neonatal; Newborn Infant; Outcome; Parasites; Perinatal Exposure; Peripheral; Phenotype; Placenta; Plasmodium; Plasmodium falciparum; Play; Population; Positioning Attribute; Predisposition; Pregnancy; Protozoa; Research; Risk; Role; Severities; Source; Staging; Symptoms; T cell response; T-Lymphocyte; TNF gene; Testing; Time; Tuberculosis; Umbilical Cord Blood; Vaccination; Vaccines; Woman; antimicrobial; cytokine; cytotoxicity; early childhood; fetal; high risk; improved; improved functioning; infancy; killings; malaria infection; malaria transmission; microorganism antigen; neonatal exposure; neonatal immune system; neonatal immunity; neonate; pathogen; placental malaria; prenatal; prenatal exposure; response; vaccination against tuberculosis

DESCRIPTION (provided by applicant): Prenatal exposure to microbial antigens can alter neonatal immunity to pathogens, modulate responses to pediatric vaccines, and increase infant susceptibility to infections. Infants born to mothers with P. falciparum infection during pregnancy are at increased risk of developing malaria during infancy, when symptoms are most severe and the risk of dying from the infection is highest. Vγ2Vδ2 lymphocytes, a subset of γδ T cells, mount rapid responses to a broad array of infectious agents, including plasmodia and mycobacteria. Numerous observations suggest the involvement of Vγ2Vδ2 lymphocytes in controlling malaria infection, and P. falciparum infection perturbs their homeostasis in adults contracting malaria for the first time. Vγ2Vδ2 lymphocytes take part in responses to Bacille Calmette-Guérin (BCG), the vaccine against tuberculosis, which is routinely administered to neonates in Sub-Saharan Africa. Vγ2Vδ2 T cell responses are antigen specific, yet MHC unrestricted, so all individuals recognize the same antigens independently of HLA haplotypes. Our preliminary results suggest that placental malaria affects fetal Vγ2Vδ2 lymphocyte phenotype, proliferation and repertoire maturation, attenuating the selection of neonatal pathogen-reactive Vγ2Vδ2 lymphocytes. We hypothesize that strong prenatal antigen stimulation, occurring in particular during placental malaria, induces deletion of pathogen-reactive Vγ2Vδ2 lymphocytes, affecting their repertoire and reactivity in neonates. This might have clinical impacts, contributing to increased malaria morbidity and lower responses to BCG vaccination during infancy. In this perspective, we seek to address two key problems concerning the impact of maternal malaria on fetal immunity and newborn responses to pathogens or pediatric vaccines. First, we want to define the impact of placental malaria on fetal immunity by quantifying changes among γδ T cells. Second, knowing that Vγ2Vδ2 T cells respond both to P. falciparum and BCG, we will test whether changes among Vγ2Vδ2 T cells link placental malaria directly to impaired BCG reactivity in newborn. To achieve these goals, we will compare Vγ2Vδ2 lymphocyte repertoire and responses to P. falciparum and BCG in three exposure groups of neonates and infants: no prenatal exposure to malaria, prenatal exposure to maternal peripheral infection with no placental involvement, and prenatal exposure to placental infection. Our long-term goal is to capitalize on our understanding of immune mechanisms at the fetal-maternal interface for developing intervention strategies to improve responses to pediatric vaccinations.

描述（由申请人提供）： 产前接触微生物抗原可以改变新生儿对病原体的免疫力，调节对儿科疫苗的反应，并增加婴儿对感染的易感性。怀孕期间感染恶性疟原虫的母亲所生的婴儿在婴儿期患疟疾的风险增加，此时症状最严重，死于感染的风险也最高。 Vγ2Vδ2 淋巴细胞是 γδ T 细胞的一个子集，可对多种感染原（包括疟原虫和分枝杆菌）做出快速反应。大量观察结果表明，Vγ2Vδ2 淋巴细胞参与控制疟疾感染，恶性疟原虫感染首次扰乱了感染疟疾的成年人的体内平衡。 Vγ2Vδ2 淋巴细胞参与对卡介苗 (BCG) 的反应，卡介苗是一种抗结核疫苗，撒哈拉以南非洲地区的新生儿通常接种该疫苗。 Vγ2Vδ2 T 细胞反应是抗原特异性的，但 MHC 不受限制，因此所有个体都能独立于 HLA 单倍型识别相同的抗原。我们的初步结果表明，胎盘疟疾影响胎儿 Vγ2Vδ2 淋巴细胞表型、增殖和全部成熟，减弱新生儿病原体反应性 Vγ2Vδ2 淋巴细胞的选择。我们假设强烈的产前抗原刺激，特别是在胎盘疟疾期间发生，会诱导 删除病原体反应性 Vγ2Vδ2 淋巴细胞，影响其在新生儿中的功能和反应性。这可能会产生临床影响，导致婴儿期疟疾发病率增加和卡介苗接种反应降低。从这个角度来看，我们寻求解决两个关键问题：孕产妇疟疾对胎儿免疫力的影响以及新生儿对病原体或儿科疫苗的反应。首先，我们希望通过量化 γδ T 细胞的变化来确定胎盘疟疾对胎儿免疫的影响。其次，知道 Vγ2Vδ2 T 细胞对恶性疟原虫和卡介苗都有反应，我们将测试 Vγ2Vδ2 T 细胞的变化是否将胎盘疟疾与新生儿 BCG 反应性受损直接联系起来。为了实现这些目标，我们将比较新生儿和婴儿的三个暴露组中的 Vγ2Vδ2 淋巴细胞库以及对恶性疟和卡介苗的反应：产前未暴露于疟疾、产前暴露于无胎盘受累的母体周围感染以及产前暴露于胎盘感染。我们的长期目标是利用我们对母婴界面免疫机制的理解来制定干预策略，以改善对儿科疫苗接种的反应。