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: 8608480
• 负责人: Cristiana Cairo
• 金额: $ 37.44万
• 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 2017-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8608480
• 关键词: Address; Adult; Affect; Africa South of the Sahara; African; Age-Years; Antigens; Attenuated; Birth; Blood; Blood Circulation; Blood specimen; 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; Interferons; 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; T-Lymphocyte Subsets; TNF gene; Testing; Time; Tuberculosis; Umbilical Cord Blood; Vaccination; Vaccines; Woman; antimicrobial; cytokine; cytotoxicity; early childhood; fetal; high risk; improved; improved functioning; infancy; killings; microorganism antigen; neonatal exposure; neonate; pathogen; prenatal; prenatal exposure; public health relevance; response; transmission process

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. V?2V¿2 lymphocytes, a subset of ?¿ T cells, mount rapid responses to a broad array of infectious agents, including plasmodia and mycobacteria. Numerous observations suggest the involvement of V?2V¿2 lymphocytes in controlling malaria infection, and P. falciparum infection perturbs their homeostasis in adults contracting malaria for the first time. V?2V¿2 lymphocytes take part in responses to Bacille Calmette-Gu¿rin (BCG), the vaccine against tuberculosis, which is routinely administered to neonates in Sub-Saharan Africa. V?2V¿2 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 V?2V¿2 lymphocyte phenotype, proliferation and repertoire maturation, attenuating the selection of neonatal pathogen-reactive V?2V¿2 lymphocytes. We hypothesize that strong prenatal antigen stimulation, occurring in particular during placental malaria, induces deletion of pathogen-reactive V?2V¿2 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 ?¿ T cells. Second, knowing that V?2V¿2 T cells respond both to P. falciparum and BCG, we will test whether changes among V?2V¿2 T cells link placental malaria directly to impaired BCG reactivity in newborn. To achieve these goals, we will compare V?2V¿2 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）： 产前暴露于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。在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，婴儿期症状最严重，死于感染的风险最高。V吗？2 V <$2淋巴细胞，一个子集？<$ T细胞对包括疟原虫和分枝杆菌在内的一系列传染性病原体产生快速反应。许多观察表明，参与V？2V ² 2淋巴细胞在控制疟疾感染中的作用，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。V吗？2V ² 2淋巴细胞参与对卡介苗（BCG）的反应，卡介苗是一种抗结核病的疫苗，通常用于撒哈拉以南非洲的新生儿。小维2 V <$2 T细胞反应是抗原特异性的，但MHC不受限制，因此所有个体识别相同的抗原，而不依赖于HLA单倍型。我们的初步结果表明胎盘疟疾影响胎儿V？2 V <$2淋巴细胞表型、增殖和库成熟，减弱新生儿病原体反应性V？2 V <$2淋巴细胞。我们推测，强烈的产前抗原刺激，特别是发生在胎盘疟疾，诱导 病原体反应性V的缺失？2 V <$2淋巴细胞，影响其在新生儿中的库和反应性。这可能会产生临床影响，导致疟疾发病率增加，婴儿期对卡介苗接种的反应降低。从这个角度来看，我们试图解决两个关键问题，母体疟疾对胎儿免疫和新生儿对病原体或儿科疫苗的反应的影响。首先，我们想通过量化以下因素的变化来确定胎盘疟疾对胎儿免疫的影响：T细胞。第二，知道V？2 V <$2 T细胞对恶性疟原虫和卡介苗都有反应，我们将测试V？2 V <$2 T细胞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V？2V ² 2.新生儿和婴儿三个暴露组的淋巴细胞库和对恶性疟原虫和卡介苗的反应：产前未暴露于疟疾，产前暴露于母体外周感染但无胎盘受累，产前暴露于胎盘感染。我们的长期目标是利用我们对胎儿-母体界面免疫机制的理解，制定干预策略，以改善对儿科疫苗接种的反应。