Fetal Immunity of Malaria

描述（由申请方提供）：抗原从母体经胎盘转移至胎儿，通常在某些情况下产生胎儿免疫应答，或在其他情况下产生胎儿免疫耐受。在发展中国家，经胎盘抗原转移特别常见，因为孕妇经常受到一种或多种慢性感染的影响。经胎盘转移如何发生，胎儿产生的反应的性质和种类，以及产前暴露对随后的儿童免疫的影响仍然知之甚少。 对这些胎儿免疫反应的更深入了解在许多领域具有广泛的应用，特别是母胎医学和新生儿护理。产前暴露于外源性抗原可能会影响早期生命中先天性和适应性免疫应答的成熟和可能的“印记”，并且这种早期暴露于感染因子或抗原可能是有益的或有害的。在妊娠期疟疾中，被寄生的红细胞（irbc）在胎盘中隔离，irbc或其可溶性产物在妊娠期间穿过胎盘，引发或耐受胎儿免疫反应。在那些表现出免疫耐受的新生儿中，我们已经显示出对恶性疟疾感染的易感性增加，直到3岁。这种耐受性是否会影响整个儿童期对恶性疟或间日疟疾病的易感性尚不清楚。同样不清楚的是为什么只有一些新生儿获得耐受表型。介导这种耐受性的免疫机制知之甚少。越来越多的证据支持这一假设，即获得性免疫耐受是一种主动形式的免疫抑制，而不是一种被动的功能缺陷发生在胎儿发育过程中，是由调节性T细胞（T细胞）介导。在这里，我们假设，产前暴露于疟疾抗原诱导胎儿疟疾特异性T细胞，持续到儿童期，抑制保护性免疫反应，通常会减轻疾病的严重程度。我们进一步假设胎儿接触疟疾抗原的时间决定了是否获得免疫耐受或胎儿启动。为了检验这些假设，我们将利用一个正在进行的项目，由妊娠期疟疾联盟，其中妇女将被随机接受强化疟疾预防整个怀孕或标准治疗，包括一次性预防。将招募14至26周胎龄的女性，导致妊娠期间预防的时间可变（因此疟疾暴露的时间可变）。 公共卫生相关性：本研究将检查子宫内暴露于疟疾血液阶段抗原对胎儿免疫应答发育的影响，以及胎儿是否对这些抗原有致敏或耐受性。我们将在巴布亚新几内亚疟疾高度流行的地区进行一项前瞻性出生队列研究，以确定胎儿接触疟疾和获得的免疫反应类型是否会影响幼儿对恶性疟或间日疟的易感性。

DESCRIPTION (provided by applicant): Transplacental transfer of antigens from mother to fetus often occurs producing a fetal immune response in some cases or fetal immune tolerance in others. In developing countries, transplacental antigen transfer is especially common, since pregnant women are often affected by one or more chronic infections. How transplacental transfer occurs, the nature and variety of the fetal responses generated, and the impact of prenatal exposure on subsequent childhood immunity remain poorly understood. Greater understanding of these fetal immune responses has broad applications in a host of areas, most especially maternal-fetal medicine and neonatal care. Prenatal exposure to exogenous antigens may affect maturation and possible "imprinting" of both innate and adaptive immune responses in early life and such early exposure to infectious agents or antigens can be beneficial or detrimental. In malaria in pregnancy, parasitized erythrocytes (irbc) sequester in the placenta and irbcs or their soluble products cross the placenta during gestation, either priming or tolerizing the fetal immune response. In those newborns who demonstrate immune tolerance, we have shown increased susceptibility to falciparum malaria infection up to 3 years of age. Whether this tolerance affects susceptibility to falciparum or vivax malaria illness throughout childhood is not known. Also unclear is why only some newborns acquire the tolerant phenotype. The immunologic mechanisms mediating this tolerance are poorly understood. Increasing evidence supports the hypothesis that acquired immune tolerance is an active form of immune suppression, rather than a passive functional defect occurring during fetal development and is mediated by regulatory T cells (Tregs). Here we hypothesize that prenatal exposure to malaria antigens induces fetal malaria-specific Tregs that persist into childhood, inhibiting protective immune responses that would normally attenuate severity of illness. We further hypothesize that the timing of fetal exposure to malaria antigens determines whether immune tolerance or fetal priming is acquired. To test these hypotheses we will take advantage of an ongoing project supported by the Malaria in Pregnancy Consortium, where women will be randomized to receive either intensive malaria prophylaxis throughout pregnancy or standard therapy consisting of one-time prophylaxis. Women between 14 and 26 weeks of gestational age will be recruited, resulting in variable timing of prophylaxis (and thus variable timing of malaria exposure) during gestation. PUBLIC HEALTH RELEVANCE: This study will examine the impact of in utero exposure to malaria blood stage antigens on development of fetal immune responses, and whether the fetus is primed or tolerized to these antigens. We will conduct a prospective birth cohort study in an area highly endemic for malaria in Papua New Guinea to determine whether the fetal exposure to malaria and type of immune response acquired affects susceptibility to falciparum or vivax malaria in early childhood.