Antibody-dependent cellular phagocytosis by human breastmilk leukocytes: impact of antibody class, stage of lactation, and target size

项目摘要 艾滋病毒母婴传播(MTCT)在资源有限的国家仍然是一个危机，在这些国家，艾滋病毒 很流行。每年大约发生20万例艾滋病毒母婴传播，其中多达一半的感染是由于 通过母乳(BM)暴露[1，2]。然而，只有约10%-15%的由感染艾滋病毒的母亲母乳喂养的婴儿实际上 被感染，表明BM本身具有很强的保护作用[1-5]。尽管多项研究表明 证明了人骨髓对HIV MTCT的保护作用[1-10]，牛奶细胞的贡献 尽管有证据表明母体白细胞的功能超出了 摄取部位[11-15]。唯一显示疗效的临床艾滋病毒疫苗试验，RV144和许多其他 研究表明，恒定(Fc)抗体结构域介导的活性与预防HIV感染相关 对其他病原体也有类似的记载[16-29]。尽管演示为必要的 清除大量病毒感染，一种基本的Fc介导的反应--抗体依赖的细胞 吞噬细胞吞噬作用(ADCP)--在艾滋病毒的背景下研究相对不足，特别是在 预防母婴传播[30-37]。初乳吞噬细胞可执行细菌、寄生虫和酵母的ADCP 用母体抗体调理；然而，关于艾滋病毒或艾滋病毒感染细胞还没有研究[38- 44]。此外，ADCP对预防艾滋病毒母婴传播的潜在贡献还没有研究过。 关于吞噬目标大小的影响(例如，无细胞和细胞相关病毒)，或 BM在哺乳期的动态白细胞组成[45-50]。只有相互矛盾的和/或小规模的研究 关于抗体亚类在Fc介导的活性中的相关性，特别是在BM中[16，42， 51-57]。鉴于目前对业务管理的ADCP活动的潜在贡献的认识存在很大差距 吞噬细胞预防母婴传播HIV，关键是要多维、全面地发展 骨髓相关原代细胞对ADCP的理解。这项拟议的研究旨在填补这方面的知识 差距。目标1将解决吞噬靶点大小/类型对骨髓细胞ADCP的影响，目标2将解决 抗体类对骨髓细胞ADCP的影响，AIM 3将解决骨髓成熟对ADCP的影响 ADCP活性。这些数据将使现场更好地了解ADCP介导的潜在贡献 通过骨髓细胞来降低HIV的MTCT，并很可能适用于其他威胁 婴儿在哺乳过程中的健康状况。

Project Summary Mother-to-child transmission (MTCT) of HIV remains a crisis in resource-limited countries where HIV is prevalent. Approximately 200,000 MTCTs of HIV occur annually, with as many as half of infections being due to exposure via breastmilk (BM) [1, 2]. Yet, only ~10-15% of infants breastfed by HIV-infected mothers actually become infected, suggesting a strong protective effect of BM itself [1-5]. Though multiple studies have demonstrated the protective effect of human BM against HIV MTCT [1-10], the contribution of the milk’s cellular component has been relatively overlooked, despite evidence that maternal leukocytes are functional beyond the sites of ingestion [11-15]. The only clinical HIV vaccine trial to show efficacy, RV144, and many other studies have correlated activities mediated by the constant (Fc) Ab domain with protection from HIV acquisition and this is documented similarly with other pathogens [16-29]. Though demonstrated as necessary for the clearance of numerous viral infections, one essential Fc-mediated response--Ab-dependent cellular phagocytosis (ADCP)--has been relatively understudied in the context of HIV, particularly in the case of prevention of MTCT [30-37]. Colostral phagocytes can perform ADCP of bacteria, parasites and yeast opsonized with maternal Abs; however, this has not been studied with regard to HIV or HIV-infected cells [38- 44]. Furthermore, the potential contribution of ADCP to protection from MTCT of HIV has not been studied with regard to impact of phagocytic target size (e.g., cell-free and cell-associated virus), or the effects of the dynamic leukocyte composition of BM over the lactation period [45-50]. Only conflicting and/or small studies have been conducted regarding the relevance of Ab subclass in Fc-mediated activity, especially in BM [16, 42, 51-57]. Given the substantial gap in present knowledge of the potential contribution of ADCP activity by BM phagocytes to prevention of MTCT of HIV, it is critical to develop a multidimensional, comprehensive understanding of ADCP by the relevant primary cells in BM. The proposed study aims to fill this knowledge gap. AIM 1 will address the impact of phagocytic target size/type on ADCP by BM cells, AIM 2 will address the impact of Ab class on ADCP by BM cells, and AIM 3 will address the impact of BM maturation over time on ADCP activity. These data will allow the field to better understand the potential contribution of ADCP mediated by BM cells to the reduction of MTCT of HIV, and may well be applicable to other pathogens that threaten infants over the course of lactation.