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

人母乳白细胞的抗体依赖性细胞吞噬作用：抗体类别、哺乳阶段和目标大小的影响

• 批准号: 10222911
• 负责人: Rebecca Powell
• 金额: $ 6.39万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10222911
• 关键词: Address; Antibodies; Antibody Formation; Bacteria; Breast Feeding; Breastfed infant; Cells; Clinical; Colostrum; Conflict (Psychology); Country; Data; Exposure to; HIV; HIV Infections; HIV vaccine; Human; Human Milk; Infant; Infection; Ingestion; Knowledge; Lactation; Leukocytes; Mediating; Milk; Mother-to-child HIV transmission; Mothers; Parasites; Phagocytes; Phagocytosis; Prevention; Resources; Risk; Role; Satellite Viruses; Site; Time; Vertical Disease Transmission; Virus; Virus Diseases; Yeasts; antibody-dependent cellular phagocytosis; lactation period; pathogen; prevent; protective effect; vaccine trial

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.

项目摘要 艾滋病毒的母亲到孩子传播（MTCT）仍然是艾滋病毒所在的资源有限国家的危机 流行。每年大约有200,000 MTCT的HIV发生，多达一半的感染应应得 通过母乳（BM）暴露[1，2]。然而，实际上，只有约10-15％的婴儿被艾滋病毒感染的母亲母乳喂养 被感染，表明BM本身具有强大的保护作用[1-5]。尽管多个研究有 证明了人类BM对HIV MTCT的受保护作用[1-10]，牛奶细胞的贡献 组成部分被相对忽略了，dospite证据表明，Mater Liukocytes功能超出 摄入的部位[11-15]。唯一显示效率RV144的临床HIV疫苗试验和许多其他 研究已将由常数（FC）AB域介导的活动与抗HIV获取的保护有关 这与其他病原体相似[16-29]。尽管证明是必要的 众多病毒感染的清除率，一种基本的FC介导的反应 - 依赖性细胞 吞噬作用（ADCP） - 在艾滋病毒的背景下相对了解，特别是在 预防MTCT [30-37]。乳腺癌细胞可以执行细菌，寄生虫和酵母菌的ADCP 用母体ABS调整；但是，这尚未研究HIV或HIV感染细胞[38-- 44]。此外，ADCP对保护HIV MTCT的潜在贡献尚未与 关注吞噬靶标大小（例如，无细胞和相关病毒）的影响，或 BM在泌乳期间的动态白细胞组成[45-50]。只有冲突和/或小型研究 已经进行了有关AB子类在FC介导的活性中的相关性，特别是在BM中[16，42， 51-57]。考虑到BM的ADCP活性的潜在贡献的当前知识存在很大的差距 吞噬对预防艾滋病毒MTCT的吞噬细胞，开发多维，全面至关重要 BM中相关原代细胞对ADCP的理解。拟议的研究旨在填补这一知识 差距。 AIM 1将解决BM细胞对ADCP的吞噬目标大小/类型的影响，AIM 2将解决 AB类对BM细胞的影响对ADCP的影响，AIM 3将解决BM成熟的影响随着时间的流逝的影响 ADCP活动。这些数据将使该领域能够更好地了解ADCP介导的潜在贡献 通过BM细胞减少HIV的MTCT，很可能适用于其他威胁的病原体 婴儿在哺乳过程中。

项目成果

Phagocytosis of a Model Human Immunodeficiency Virus Target by Human Breast Milk Leukocytes Is Predominantly Granulocyte-Driven When Elicited by Specific Antibody.

当特定抗体引发时，人母乳白细胞对人类免疫缺陷病毒模型靶标的吞噬作用主要是粒细胞驱动的。

• DOI: 10.1089/bfm.2018.0232
• 发表时间: 2019
• 期刊: Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine
• 作者: Powell,RebeccaLR;Fox,Alisa;Liu,Xiaomei;Itri,Vincenza
• 通讯作者: Itri,Vincenza

Impact of IgG Isotype on the Induction of Antibody-Dependent Cellular Phagocytosis of HIV by Human Milk Leukocytes.

• DOI: 10.3389/fimmu.2022.831767
• 发表时间: 2022
• 期刊: Frontiers in immunology
• 影响因子: 7.3

Isolation of Leukocytes from Human Breast Milk for Use in an Antibody-dependent Cellular Phagocytosis Assay of HIV Targets.

从人母乳中分离白细胞，用于 HIV 靶标的抗体依赖性细胞吞噬测定。

• DOI: 10.3791/60149
• 发表时间: 2019
• 期刊: Journal of visualized experiments : JoVE
• 作者: Powell,RebeccaLR;Fox,Alisa
• 通讯作者: Fox,Alisa