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 外周血单核细胞 瞄准的 艾滋病毒+孕妇 （干扰素 之中 1a 怀孕 展示 表型 CFP-10 母亲的 血清学 母亲的 转移 数据 第一的 比较的 使用 细胞计数术 理解 女性 揭露 全球 20 亿人口患有潜伏结核分枝杆菌 (Mtb) 感染 (LTBI) 大约 10% 进展为活动性结核病。结核病是婴儿死亡的主要原因， 2015 年，有 240,000 名儿童死亡。5 岁以下儿童死于结核病的风险高出 3 倍。 与年龄较大的孩子相比的年龄。尽管正在付出很大努力来开发有效的结核病 卡介苗仍然是唯一获得批准的结核病疫苗。尽管接种了卡介苗，婴儿仍有很高的感染风险 新发结核感染 (TBI) 以及 LTBI 进展为活动性结核病。免疫方面的文献 在暴露于艾滋病毒的未感染婴儿中的情况尚无定论。 Th2 偏向的作用和 调节性 T 细胞 (T regs) 的数量也需要考虑。对于此提案，我们可以访问 以及来自已完成的 IMPAACT 试验 (P1078) 的母婴样本血浆。这项研究是 测试妊娠期间或产后异烟肼预防性治疗 (IPT) 的安全性 那些被追踪到产后一年的女性。 IGRA 测试了 LTBI 的发生率 伽玛释放测定）。大约 30% 的女性在进入研究时呈 IGRA 阳性。 婴儿中，大约 5.6% 在第 12 周时呈 IGRA +，并在第 44 周时保持阳性。瞄准 我们将检验以下假设：在母亲患有 LTBI 的情况下，暴露于 HIV 的未感染 (HEU) 婴儿 在子宫内对分枝杆菌抗原敏感，形成对 Mtb 的免疫记忆， 对卡介苗疫苗接种的反应发生改变。为此，我们将对 CD4 T 细胞进行详细分析 子集以及对 RD-1 抗原的抗原特异性细胞内细胞因子记忆反应 和 ESAT-6，一种 DosR 潜伏抗原，并通过流式细胞术检测 PPD。在目标 2 中，我们假设 Mtb抗体等因素可以影响婴儿的免疫反应。为了这个目标，系统 FcR 结合抗体的生物物理和功能表征方法将在 分娩时的血浆以及第 12 周和第 44 周时的婴儿血浆，用于确定被动寿命 母体抗体。细胞因子概况、原籍国和怀孕期间的 IPT 将包含在 母婴免疫力分析。在目标 3 中，我们假设诊断出 LTBI 的婴儿在 生命年的单核细胞和抗原特异性 CD4+ T 细胞具有不同的基因转录组谱 未感染结核病的人。为此，我们将分析 CD4 T 细胞和单核细胞 单细胞转录组学。转录谱将通过流与免疫学谱相关联 目标 1 和 2 中描述的系统血清学分析和抗体谱 这些研究与 HIV+ LTBI 背景下母婴相互作用的免疫学机制 及其 EUI，以及对 BCG 疫苗反应的影响。重要的是他们有潜力 LTBI 的敏感生物标志物并产生与疫苗策略相关的信息。 卡介苗 疫苗 第956章 。