Fetal Immunity of Malaria

描述（由申请人提供）：抗原经胎盘从母亲转移到胎儿经常发生，在某些情况下产生胎儿免疫反应，在其他情况下产生胎儿免疫耐受。在发展中国家，经胎盘抗原转移尤其普遍，因为孕妇经常受到一种或多种慢性感染的影响。胎盘移植是如何发生的，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。更好地了解这些胎儿免疫反应在许多领域有广泛的应用，尤其是母胎医学和新生儿护理。产前暴露于外源性抗原可能影响生命早期先天和适应性免疫反应的成熟和可能的“印记”，这种早期暴露于传染性病原体或抗原可能是有益的或有害的。在妊娠期疟疾中，寄生红细胞（irbc）在胎盘中被隔离，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，我们已经表明，在3岁之前，对恶性疟疾感染的易感性增加。这种耐受性是否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性表型。介导这种耐受性的免疫机制尚不清楚。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，而不是胎儿发育过程中发生的由调节性T细胞（Tregs）介导的被动功能缺陷。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treg持续到童年，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暴露于疟疾抗原的时间决定了是否获得免疫耐受或胎儿启动。为了验证这些假设，我们将利用由妊娠期疟疾联盟支持的一个正在进行的项目，在该项目中，妇女将被随机分组，在整个妊娠期间接受强化疟疾预防，或接受包括一次性预防在内的标准治疗。将招募14至26周孕龄的妇女，导致妊娠期间预防的时间不同（因此接触疟疾的时间也不同）。

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.