Immune correlates of LTBI in HIV-exposed infants

HIV 暴露婴儿 LTBI 的免疫相关性

• 批准号: 10543401
• 负责人: Savita Pahwa
• 金额: $ 57.57万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-05 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543401
• 关键词: Affect; Age; Age Years; Antibodies; Antigens; Area; BCG Live; BCG Vaccine; Bacille Calmette-Guerin vaccination; Binding; Biological Assay; Biological Markers; Birth; Blood; Breast Feeding; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Cell Maturation; Cells; Cessation of life; Characteristics; Child; Childhood; Clinical; Clinical Trials; Collaborations; Color; Country; Cytometry; Data; Data Analyses; Development; Diagnosis; Diagnostic tests; Disease; Enrollment; Exercise; Flow Cytometry; Gene Expression Profile; Genes; Gold; HIV; HIV Infections; HIV-exposed uninfected infant; Helper-Inducer T-Lymphocyte; IL17 gene; Immune; Immune checkpoint inhibitor; Immune response; Immunity; Immunoglobulin A; Immunoglobulin G; Immunoglobulin M; Immunologic Memory; Immunologic Tests; Immunologics; Immunology; Incidence; Individual; Infant; Infant Development; Infant Mortality; Infection; Intake; Interferons; Interleukin-2; International Maternal Pediatric Adolescent AIDS Clinical Trials; Laboratories; Life; Literature; Longevity; Maternally-Acquired Immunity; Measures; Mediating; Memory; Meningeal Tuberculosis; Miliary Tuberculosis; Mothers; Mycobacterium bovis; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Newborn Infant; Participant; Peripheral; Peripheral Blood Mononuclear Cell; Persons; Pharmaceutical Preparations; Phenotype; Plasma; Population; Postpartum Period; Pregnancy; Pregnant Women; Prevalence; Prevention therapy; Preventive therapy; Proliferating; Protocols documentation; Pulmonary Tuberculosis; Regulatory T-Lymphocyte; Research; Research Personnel; Risk; Risk Factors; Role; Sampling; Serology; Sorting; System; T-Lymphocyte Subsets; TNF gene; TNFSF5 gene; Testing; Time; Transcript; Tube; Tuberculosis; Tuberculosis Vaccines; Vaccines; Woman; Work; antenatal; biophysical techniques; cytokine; data exchange; high risk; improved; in utero; indexing; interleukin-21; interleukin-22; isoniazid; memory CD4 T lymphocyte; monocyte; mortality risk; mycobacterial; new technology; pregnant; prevent; programmed cell death protein 1; progression risk; protein purification; reactivation from latency; repository; response; safety assessment; safety testing; single-cell RNA sequencing; transcriptome; transcriptomics; tuberculosis immunity; vaccine response; vaccine strategy

Almost whom leading of vaccine, acquiring to preponderance PBMC aimed HIV+ pregnant (interferon Among 1a pregnancy show phenotypic CFP-10 maternal serology maternal transferred data first compared using cytometry understanding women uncover 2 billion of the world's population has latent Mycobacterium tuberculosis (Mtb) infection (LTBI) of approximately 10% progress to active TB disease. TB disease is a major cause of infant mortality, to 240,000 childhood deaths in 2015. The risk of death from TB is 3 times higher in children <5 yrs. age compared to older children. Although much effort is being exercised to develop an effective TB BCG is still the only approved TB vaccine. Despite BCG vaccination, infants have a high risk of new TB infections (TBI) and for progression of LTBI to active TB disease. Literature on immunity in HIV exposed uninfected infants is inconclusive. role of a Th2 bias and of regulatory T cells (T regs) also need consideration. For this proposal, we have access to and plasma of maternal-infant samples from a completed IMPAACT trial (P1078). This study was to test the safety of Isoniazid preventative therapy (IPT) during pregnancy or post-partum in women who were followed until I year post-partum. Incidence of LTBI was tested by IGRA gamma release assay). Approximately 30% of the women were IGRA positive at study entry. infants, approximately 5.6% were IGRA + at 12 weeks and remained positive at 44 weeks. In Aim we will test the hypotheses that HIV exposed uninfected (HEU) infants whose mothers have LTBI during are sensitized to mycobacterial antigens in utero, develop immunologic memory to Mtb and an altered response to BCG vaccination . For this aim we will perform detailed analyses of CD4 T cell subsets as well as antigen specific intra-cellular cytokine memory response to RD-1 antigens and ESAT-6, a DosR latency antigen and to PPD by flow cytometry. In Aim 2 we hypothesize that factors such as Ab to Mtb can influence the infant immune response . For this aim a systems approach for biophysical and functional characterization of FcR binding Ab will be performed in plasma at delivery and infant plasma at weeks 12 and 44, for ascertaining longevity of passively maternal Ab. Cytokine profile, country of origin, and IPT during pregnancy will be included in analysis of maternal-infant immunity. In Aim 3 we hypothesize that infants diagnosed with LTBI in the year of life have distinct gene transcriptomic profiles in monocytes and antigen specific CD4+ T cells to those who are not infected with TB . In this aim we will profile CD4 T cells and monocytes single cell transcriptomics. Transcriptional profiles will be correlated with immunologic profile by flow and Ab profile by systems serology described in Aims 1 and 2 These studies are relevant for immunological mechanisms of maternal-infant interaction in the context of LTBI in HIV+ and their EUI, and impact on BCG vaccine responses. Importantly they have the potential to sensitive biomarkers of LTBI and yield information relevant for vaccine strategies. BCG vaccine The 956 .

几乎 谁 领导 的 疫苗， 获取 到 优势 PBMC 瞄准 艾滋病毒+怀孕 （干扰素 之中 1a 怀孕 展示 表型 CFP-10 母亲 血清学 母亲 转移 数据 第一的 比较的 使用 细胞仪 理解 女性 揭露 世界人口中有20亿人具有潜在的分枝杆菌结核病（MTB）感染（LTBI） 大约10％的活性结核病进展。结核病是婴儿死亡率的主要原因， 2015年的儿童死亡人数为240,000。结核病死亡的风险<5年的儿童高3倍。 年龄与大儿童相比。尽管正在努力开发有效的结核病 BCG仍然是唯一经批准的结核病疫苗。尽管BCG疫苗接种，但婴儿的风险很高 新的结核病感染（TBI）和LTBI向活性结核病的发展。关于免疫的文献 在艾滋病毒中，未感染的婴儿尚无定论。 Th2偏见和 调节性T细胞（T Regs）也需要考虑。对于此建议，我们可以访问 来自完整的不分支试验的母体风格样品的血浆（P1078）。这项研究是 测试怀孕期间或产后的等异尼二氮二氮二氮化疗法的安全性 遵循的妇女直到产后我。 LTBI的发病率由IGRA测试 伽马发布测定法）。大约30％的妇女在研究进入时为IGRA阳性。 婴儿在12周时为IGRA +约5.6％，在44周时保持阳性。目标 我们将测试艾滋病毒在母亲患有LTBI的婴儿中暴露于未感染的（HEU）的假设 对子宫内分枝杆菌抗原敏感，对MTB产生免疫记忆和 对BCG疫苗接种的反应改变。为此，我们将进行CD4 T细胞的详细分析 子集以及抗原特异性细胞内细胞因子对RD-1抗原的反应 和ESAT-6，一种DOSR潜伏期抗原，通过流式细胞仪对PPD。在目标2中，我们假设 诸如AB到MTB之类的因素会影响婴儿免疫反应。为此目标 FCR结合AB的生物物理和功能表征的方法将在 分娩时的血浆和第12周和第44周的婴儿血浆，以确定被动寿命 母亲AB。细胞因子概况，原产国和怀孕期间的IPT将包括 分析产妇免疫。在AIM 3中，我们假设在 生命年份具有单核细胞和抗原特异性CD4+ T细胞的不同基因转录组谱。 对于那些未感染结核病的人。在此目标中，我们将介绍CD4 T细胞和单核细胞 单细胞转录组学。转录曲线将与流量与免疫学概况相关 AB的AB谱图AIM 1和2中描述的系统学血清学与这些研究有关 在HIV+中LTBI的背景下，产妇互动的免疫学机制 及其EUI，以及对BCG疫苗反应的影响。重要的是，他们有潜力 LTBI的敏感生物标志物和收益与疫苗策略相关的信息。 BCG 疫苗 956 。