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

项目摘要 母婴传播艾滋病毒在资源有限的国家仍然是一个危机， 普遍存在。每年约有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~10-15%的婴儿母乳喂养的艾滋病毒感染的母亲， 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， 证明了人类BM对HIV MTCT的保护作用[1-10]，乳汁中细胞的贡献 尽管有证据表明母体白细胞的功能超出了 （11-15页）唯一显示有效性的临床HIV疫苗试验，RV 144，以及许多其他 研究已经将由恒定（Fc）Ab结构域介导的活性与保护免受HIV感染相关联 这与其他病原体类似[16-29]。虽然证明是必要的， 许多病毒感染的清除，一个重要的Fc介导的反应-抗体依赖性细胞 吞噬作用（ADCP）-在HIV的背景下相对研究不足，特别是在 预防母婴传播[30-37]。初乳吞噬细胞可对细菌、寄生虫和酵母菌进行ADCP 用母体Ab调理;然而，这还没有关于HIV或HIV感染的细胞进行研究[38- 39]。 44]。此外，ADCP对预防HIV母婴传播的潜在作用尚未进行研究， 关于吞噬目标大小的影响（例如，无细胞和细胞相关病毒），或 哺乳期BM的动态白细胞组成[45-50]。仅存在冲突和/或小型研究 已经进行了关于Ab亚类在Fc介导的活性，特别是在BM中的相关性的研究[16，42， 51-57]。鉴于目前对BM ADCP活动潜在贡献的了解存在巨大差距 巨噬细胞对预防艾滋病母婴传播，至关重要的是要制定一个多方面的，全面的 通过BM中的相关原代细胞了解ADCP。这项研究旨在填补这一知识 间隙AIM 1将解决BM细胞吞噬目标大小/类型对ADCP的影响，AIM 2将解决BM细胞吞噬目标大小/类型对ADCP的影响。 Ab类对BM细胞ADCP的影响，AIM 3将解决BM随时间成熟对ADCP的影响。 ADCP活动这些数据将使该领域更好地了解ADCP介导的潜在贡献 骨髓细胞减少艾滋病毒的母婴传播，并可能适用于其他病原体的威胁， 哺乳期的婴儿。

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.