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: 8072020
• 负责人: Kathleen R Page
• 金额: $ 13.41万
• 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/8072020
• 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; Phase; Postdoctoral Fellow; Predisposition; Production; Property; Prophylactic treatment; RANTES; Recombinants; Research; Risk; Serum; Small Inducible Cytokine A3; Stigmata; Testing; Time; Tuberculosis Vaccines; Umbilical Cord Blood; Vaccinated; Vaccination; Viral Load result; Water; Woman; antiretroviral therapy; base; chemokine; chemokine receptor; clinical effect; cost; feeding; immune activation; immunogenicity; in vivo; neonate; novel; pathogen; receptor; receptor expression; skills; social stigma; stem; transmission process; vaccination against tuberculosis; 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）：该提案的目的是检验以下假设：新生儿BCG疫苗接种导致免疫反应激活，这可能会增加HIV阳性母亲母乳喂养的婴儿对HIV感染的易感性。这项调查源于候选人作为异源 ^免疫后专家的研究，并使她能够在基于患者的免疫学研究方面发展专业知识。此外，它为发展国际研究的技能提供了长期的机会，并与候选人的原籍地区拉丁美洲建立了学术合作。该建议的具体目的是评估BCG对HIV进入所需的共受体表达（CCR5和CXCR4）的影响以及单核细胞对HIV感染的敏感性。研究的初始阶段将在体外使用健康婴儿的脐带血细胞进行体外进行。将使用FACS分析来确定合作者水平，并通过表达GFP的HIV-1来测量单一HIV感染。在优化所有涉及的测定后，研究的临床阶段将进行，并将涉及健康的新生儿。该阶段是对BCG疫苗接种前后单核细胞的共受体表达和HIV敏感性的纵向评估。将在脐带血单核细胞（BCG）和外周血单单核细胞中测量激活标记和HIV敏感性，从同一婴儿获得了6周后BCG疫苗接种后获得的。通过暴露于母乳，在产后感染了通过母亲到儿童传播（MTCT）感染HIV的婴儿中很大一部分。尽管独家替代喂养可以消除通过泌乳获得艾滋病毒的风险，但由于污名，高配方奶粉或不良获取饮用水的机会，对于低收入环境中的妇女，这种选择通常是不安全或不可行的。这项研究的结果将为进一步探索BCG诱导的免疫激活对宿主对HIV的易感性的临床作用提供概念免疫学基础。 BCG对HIV进入所需的共受体的影响可能对BCG疫苗接种在受HIV暴露的母乳喂养的新生儿中的时间有影响。