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 .

差不多了 他是谁 领先 的 疫苗， 获取 至 优势 PBMC 瞄准 HIV+孕妇 (干扰素 其中 1A 妊娠 显示 表型 CFP-10 母性 血清学 母性 已转接 数据 第一 比较 使用 细胞计数法 理解 女人 揭开面纱 世界上有20亿人口患有潜在的结核分枝杆菌感染(LTBI) 活动性结核病的进展约为10%。结核病是婴儿死亡的主要原因， 2015年儿童死亡人数降至24万人。5岁儿童死于结核病的风险是前者的3倍。 与年龄较大的孩子相比。尽管正在努力开发一种有效的结核病 卡介苗仍然是唯一被批准的结核病疫苗。尽管接种了卡介苗，但婴儿患BCG的风险很高 新的结核病感染(TBI)和LTBI向活动性结核病的进展。关于免疫的文献 在暴露于艾滋病毒的未感染婴儿中，这一点尚不确定。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 和来自完成的IMPAACT试验的母婴样本的血浆(P1078)。这项研究是 为了测试异烟肼预防治疗(IPT)在孕期或产后的安全性 一直被跟踪到产后一年的女性。用IGRA对LTBI的发生率进行检验 伽马释放试验)。在研究开始时，大约30%的女性IGRA呈阳性。 婴儿中，12周时IGRA阳性的约5.6%，44周时仍为阳性。在AIM 我们将检验这样的假设，即母亲在LTBI期间接触艾滋病毒的未感染(HEU)婴儿 在子宫中对分枝杆菌抗原敏感，对结核分枝杆菌和结核分枝杆菌产生免疫记忆 对卡介苗接种的不同反应。为此，我们将对CD4T细胞进行详细的分析 RD-1抗原的亚群及抗原特异性细胞内细胞因子记忆反应 流式细胞仪检测DosR潜伏期抗原ESAT-6与PPD的结合。在目标2中，我们假设 抗结核分枝杆菌抗体等因素可影响婴儿的免疫应答。为此目的，一种系统 将在#年进行FCR结合抗体的生物物理和功能表征方法 分娩时血浆和12周和44周婴儿血浆，以确定被动的寿命 母体抗体。细胞因子概况、原产国和怀孕期间的IPT将包括在 母婴免疫状况分析。在目标3中，我们假设被诊断为LTBI的婴儿在 生命年份在单核细胞和抗原特异的CD4+T细胞中有不同的基因转录图谱 给那些没有感染结核病的人。在这个目标中，我们将分析CD4T细胞和单核细胞 单细胞转录学。转录图谱将通过Flow与免疫学图谱相关联 以及AIMS 1和AIMS 2中所述的系统血清学分析。这些研究与 HIV+LTBI背景下母婴相互作用的免疫学机制 以及它们的EUI，以及对卡介苗疫苗反应的影响。重要的是，他们有可能 LTBI的敏感生物标志物和与疫苗策略相关的产量信息。 卡介苗 疫苗 九百五十六 。