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: 9789908
• 负责人: Rebecca Powell
• 金额: $ 21.19万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9789908
• 关键词: Address; Adherence; Affect; Antibodies; Antibody Response; Antiviral Agents; Bacteria; Breast Feeding; Breastfed infant; Cells; Clinical; Colostrum; Complex; Conflict (Psychology); Country; Data; Elements; Exhibits; Exposure to; Fc Receptor; HIV; HIV Infections; HIV vaccine; Health Status; Highly Active Antiretroviral Therapy; Human; Human Milk; Immune response; Infant; Infection; Ingestion; Innate Immune System; Knowledge; Laboratories; Lactation; Leukocytes; Lymphocyte; Maternal antibody; Mediating; Milk; Mother-to-child HIV transmission; Mothers; Parasites; Phagocytes; Phagocytosis; Postpartum Period; Prevention; Property; Publishing; Resources; Risk; Role; Sampling; Satellite Viruses; Secretory Immunoglobulin A; Site; Time; Toxic effect; Vaccines; Variant; Vertical Disease Transmission; Virion; Virus; Virus Diseases; Woman; Yeasts; antibody-dependent cell cytotoxicity; discrete data; experimental study; granulocyte; individual variation; infant death; lactation period; monocyte; pathogen; preference; prevent; protective effect; response; transmission process; 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.

项目概要 在艾滋病毒流行的资源有限国家，艾滋病毒母婴传播（MTCT）仍然是一场危机 流行。每年大约发生 20 万例 HIV 母婴传播，其中多达一半的感染是由于 通过母乳接触 (BM) [1, 2]。然而，只有 10-15% 的婴儿实际上是由感染艾滋病毒的母亲母乳喂养的 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 证明了人类母乳对 HIV 母婴传播的保护作用 [1-10]，这是乳汁细胞的贡献 尽管有证据表明母体白细胞的功能超出了 摄入部位[11-15]。唯一显示疗效的临床 HIV 疫苗试验、RV144 以及许多其他疫苗 研究将恒定 (Fc) Ab 结构域介导的活性与防止 HIV 感染的保护联系起来 其他病原体也有类似的记录[16-29]。尽管已被证明是必要的 清除多种病毒感染，一种重要的 Fc 介导的反应——Ab 依赖性细胞 吞噬作用（ADCP）——在艾滋病毒的背景下，人们对吞噬作用的研究相对较少，特别是在艾滋病毒的情况下 预防母婴传播[30-37]。初乳吞噬细胞可以对细菌、寄生虫和酵母进行 ADCP 与母体 Abs 调理；然而，尚未对 HIV 或 HIV 感染细胞进行研究 [38- 44]。此外，尚未研究 ADCP 对预防 HIV 母婴传播的潜在贡献 关于吞噬目标大小（例如，无细胞和细胞相关病毒）的影响，或 哺乳期骨髓的动态白细胞组成[45-50]。仅存在冲突和/或小型研究 已经针对 Ab 亚类在 Fc 介导的活性中的相关性进行了研究，特别是在 BM 中 [16, 42, 51-57]。鉴于目前对 BM 对 ADCP 活动的潜在贡献的了解还存在巨大差距 吞噬细胞对预防艾滋病毒母婴传播至关重要，开发多维、综合的方法至关重要 BM 中相关原代细胞对 ADCP 的理解。拟议的研究旨在填补这些知识 差距。 AIM 1 将解决吞噬目标大小/类型对 BM 细胞 ADCP 的影响，AIM 2 将解决 Ab 类别对 BM 细胞 ADCP 的影响，AIM 3 将解决 BM 成熟随着时间的推移对 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 BM 细胞可减少 HIV 母婴传播，并且很可能适用于威胁其他病原体 哺乳期的婴儿。