Immunomodulatory Properties of BCG: Implications for MTCT

卡介苗的免疫调节特性：对 MTCT 的影响

• 批准号: 7419467
• 负责人: Kathleen R Page
• 金额: $ 13.32万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-05 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7419467
• 关键词: Adult; Biological Assay; Birth; Blood Cells; Breast Feeding; CCR5 gene; CD4 Lymphocyte Count; CXCR4 gene; Cells; Child; Childhood; Clinical; Collaborations; Evaluation; Exposure to; Fostering; Foundations; Future; Green Fluorescent Proteins; HIV; HIV Infections; HIV Seropositivity; HIV-1; Human Milk; Immune; Immune response; Immunity; Immunologics; Immunology; In Vitro; Incidence; Infant; Infection; International; Investigation; Lactation; Latin America; Low income; Measures; Mononuclear; Mothers; Neonatal; Patients; Perinatal; Peripheral Blood Mononuclear Cell; Personal Satisfaction; Phase; Postdoctoral Fellow; Predisposition; Production; Property; Prophylactic treatment; Purpose; Recombinants; Research; Research Personnel; Risk; Serum; Small Inducible Cytokine A3; Stigmata; Testing; Time; Tuberculosis Vaccines; Umbilical Cord Blood; Vaccinated; Vaccination; Viral Load result; Water; Week; Woman; antiretroviral therapy; base; chemokine; chemokine receptor; clinical effect; cost; feeding; immunogenicity; in vivo; neonate; novel; pathogen; programs; receptor; receptor expression; skills; social stigma; stem; transmission process; vaccination strategy

DESCRIPTION (provided by applicant): The purpose of this proposal is to test the hypothesis that neonatal BCG vaccination leads to activation of immune response that may increase the susceptibility to HIV infection in breast-fed infants of HIV-positive mothers. This investigation stems from the candidate's research as a post-doctoral fellow in heterologous ^ immunity and will allow her to develop expertise in patient-based immunology research. Furthermore, it provides a long-sought opportunity to develop skills in international research and foster an academic collaboration with Latin America, the candidate's region of origin. The specific aim of this proposal is to evaluate the effect of BCG on expression of co-receptors required for HIV entry (CCR5 and CXCR4) and on susceptibility of mononuclear cells to HIV infection. The initial phase of the study will be performed in vitro, using cord blood cells from healthy infants. Determination of co- receptors levels will be performed using FACS analysis and single-round HIV infection will be measured with a recombinant GFP-expressing HIV-1. The clinical phase of the study will proceed after optimization of all assays involved, and will involve healthy neonates. This phase is a longitudinal assessment of co-receptor expression and HIV susceptibility of mononuclear cells before and after BCG vaccination. Activation markers and HIV susceptibility will be measured in cord blood mononuclear cells (pre-BCG) and peripheral blood mononuclear cells obtained from the same infants 6 weeks'after BCG vaccination. A significant proportion of infants infected with HIV through maternal-to-child-transmission (MTCT) are infected in the post-partum period through exposure to breastmilk. Although exclusive replacement feeding eliminates the risk of HIV acquisition through lactation, this option is often not safe or feasible for women in lower income settings due to stigma, high cost of formula, or poor access to potable water. The results from this study will provide a conceptual immunologic basis for further exploring the clinical effect of BCG-induced immune activation on host susceptibility to HIV. The effect of BCG on co-receptors required for HIV entry may have implications regarding the timing of BCG vaccination in HIV-exposed breastfed neonates.

描述（由申请人提供）：本提案的目的是检验以下假设：新生儿 BCG 疫苗接种会导致免疫反应激活，从而可能增加 HIV 阳性母亲母乳喂养的婴儿对 HIV 感染的易感性。这项研究源于候选人作为异源免疫博士后研究员的研究，将使她能够发展基于患者的免疫学研究的专业知识。此外，它还提供了一个期待已久的机会，可以培养国际研究技能，并促进与候选人的原籍拉丁美洲的学术合作。该提案的具体目的是评估 BCG 对 HIV 进入所需的辅助受体（CCR5 和 CXCR4）表达以及单核细胞对 HIV 感染的易感性的影响。该研究的初始阶段将在体外进行，使用健康婴儿的脐带血细胞。将使用FACS分析来确定共受体水平，并且将使用表达重组GFP的HIV-1来测量单轮HIV感染。该研究的临床阶段将在所有相关分析优化后继续进行，并将涉及健康的新生儿。此阶段是对 BCG 疫苗接种前后单核细胞的辅助受体表达和 HIV 易感性的纵向评估。在接种 BCG 疫苗 6 周后，将在从同一婴儿获得的脐带血单核细胞（BCG 前）和外周血单核细胞中测量激活标记和 HIV 易感性。通过母婴传播（MTCT）感染艾滋病毒的婴儿中有很大一部分是在产后通过接触母乳而感染的。尽管纯替代喂养消除了通过哺乳感染艾滋病毒的风险，但由于耻辱感、配方奶成本高或难以获得饮用水，这种选择对于低收入环境中的妇女来说通常不安全或不可行。本研究结果将为进一步探讨卡介苗诱导的免疫激活对宿主艾滋病毒易感性的临床效果提供概念性免疫学基础。 BCG 对 HIV 进入所需的辅助受体的影响可能会对暴露于 HIV 的母乳喂养新生儿的 BCG 疫苗接种时机产生影响。