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 旨在 艾滋病毒阳性孕妇 （干扰素 之间 1a 妊娠 显示 表型 CFP-10 产妇 血清学 产妇 转移 数据 第一 相比 使用 细胞术 理解 妇女 揭开 世界上有20亿人口患有潜伏性结核分枝杆菌（Mtb）感染（LTBI）， 约10%进展为活动性结核病。结核病是婴儿死亡的一个主要原因， 24万儿童死亡。5岁以下儿童死于结核病的风险高3倍。 与年龄较大的孩子相比。尽管人们正在努力开发一种有效的结核病治疗方法， 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，婴儿仍有很高的风险， 新的TB感染（TBI）和LTBI进展为活动性TB疾病。关于免疫的文献 在未感染艾滋病毒的婴儿中的作用尚不确定。Th 2偏好的作用， 调节性T细胞（T细胞）也需要考虑。对于此提案，我们可以访问 和来自已完成的IMPAACT试验（P1078）的母婴样本的血浆。本研究 在妊娠期间或产后测试异烟肼预防性治疗（IPT）的安全性， 产后1年随访的妇女。用IGRA检验LTBI的发生率 γ释放测定）。大约30%的女性在进入研究时是IGRA阳性。 婴儿中，约5.6%在12周时为IGRA +，并在44周时保持阳性。在Aim中 我们将检验以下假设： 在子宫内对分枝杆菌抗原敏感，对Mtb产生免疫记忆， 对卡介苗接种的反应改变为此，我们将对CD 4 T细胞进行详细的分析。 以及对RD-1抗原的抗原特异性细胞内细胞因子记忆应答 和ESAT-6，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， 抗结核抗体等因素可影响婴儿免疫应答。为此，系统 FcR结合Ab的生物物理和功能表征方法将在 分娩时的血浆和第12周和第44周的婴儿血浆，用于确定被动 母体抗体将纳入妊娠期间的细胞因子谱、来源国和IPT， 母婴免疫分析。在目标3中，我们假设， 在单核细胞和抗原特异性CD 4 + T细胞中， 给那些没有感染结核病的人。在这个目标中，我们将分析CD 4 T细胞和单核细胞 单细胞转录组学通过流式细胞术将转录谱与免疫学谱相关联 目的1和2中所述的系统血清学和Ab谱 HIV+患者LTBI背景下母婴相互作用的免疫学机制 及其EUI，以及对BCG疫苗应答的影响。重要的是，它们有可能 LTBI的敏感生物标志物，并产生与疫苗策略相关的信息。 BCG 疫苗The 956 .