Immune correlates of LTBI in HIV-exposed infants
HIV 暴露婴儿 LTBI 的免疫相关性
基本信息
- 批准号:10543401
- 负责人:
- 金额:$ 57.57万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:AffectAgeAge YearsAntibodiesAntigensAreaBCG LiveBCG VaccineBacille Calmette-Guerin vaccinationBindingBiological AssayBiological MarkersBirthBloodBreast FeedingCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCell MaturationCellsCessation of lifeCharacteristicsChildChildhoodClinicalClinical TrialsCollaborationsColorCountryCytometryDataData AnalysesDevelopmentDiagnosisDiagnostic testsDiseaseEnrollmentExerciseFlow CytometryGene Expression ProfileGenesGoldHIVHIV InfectionsHIV-exposed uninfected infantHelper-Inducer T-LymphocyteIL17 geneImmuneImmune checkpoint inhibitorImmune responseImmunityImmunoglobulin AImmunoglobulin GImmunoglobulin MImmunologic MemoryImmunologic TestsImmunologicsImmunologyIncidenceIndividualInfantInfant DevelopmentInfant MortalityInfectionIntakeInterferonsInterleukin-2International Maternal Pediatric Adolescent AIDS Clinical TrialsLaboratoriesLifeLiteratureLongevityMaternally-Acquired ImmunityMeasuresMediatingMemoryMeningeal TuberculosisMiliary TuberculosisMothersMycobacterium bovisMycobacterium tuberculosisMycobacterium tuberculosis antigensNewborn InfantParticipantPeripheralPeripheral Blood Mononuclear CellPersonsPharmaceutical PreparationsPhenotypePlasmaPopulationPostpartum PeriodPregnancyPregnant WomenPrevalencePrevention therapyPreventive therapyProliferatingProtocols documentationPulmonary TuberculosisRegulatory T-LymphocyteResearchResearch PersonnelRiskRisk FactorsRoleSamplingSerologySortingSystemT-Lymphocyte SubsetsTNF geneTNFSF5 geneTestingTimeTranscriptTubeTuberculosisTuberculosis VaccinesVaccinesWomanWorkantenatalbiophysical techniquescytokinedata exchangehigh riskimprovedin uteroindexinginterleukin-21interleukin-22isoniazidmemory CD4 T lymphocytemonocytemortality riskmycobacterialnew technologypregnantpreventprogrammed cell death protein 1progression riskprotein purificationreactivation from latencyrepositoryresponsesafety assessmentsafety testingsingle-cell RNA sequencingtranscriptometranscriptomicstuberculosis immunityvaccine responsevaccine strategy
项目摘要
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
.
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Savita Pahwa其他文献
Savita Pahwa的其他文献
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{{ item.author }}
{{ truncateString('Savita Pahwa', 18)}}的其他基金
Immunity and HIV persistence in perinatal HIV infection
围产期 HIV 感染中的免疫和 HIV 持续性
- 批准号:
9211649 - 财政年份:2016
- 资助金额:
$ 57.57万 - 项目类别:
Immunity and HIV persistence in perinatal HIV infection
围产期 HIV 感染中的免疫和 HIV 持续性
- 批准号:
9302666 - 财政年份:2016
- 资助金额:
$ 57.57万 - 项目类别:
Antibody Responses in Aging SIV Infected Monkeys
感染 SIV 的衰老猴子的抗体反应
- 批准号:
9120783 - 财政年份:2015
- 资助金额:
$ 57.57万 - 项目类别:
Immune Activation in Virologically Suppressed Indian HIV-infected Patients
病毒学受到抑制的印度艾滋病毒感染者的免疫激活
- 批准号:
8540075 - 财政年份:2013
- 资助金额:
$ 57.57万 - 项目类别:
Immune Activation in Virologically Suppressed Indian HIV-infected Patients
病毒学受到抑制的印度艾滋病毒感染者的免疫激活
- 批准号:
8728729 - 财政年份:2013
- 资助金额:
$ 57.57万 - 项目类别:
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