DYNAMICS OF M. TUBERCULOSIS-SPECIFIC INNATE AND ADAPTIVE IMMUNITY DURING PREGNANCY AND POSTPARTUM IN WOMEN WITH HIV

HIV 感染女性妊娠期和产后结核分枝杆菌特异性先天性和适应性免疫的动态

基本信息

批准号：
10356601
负责人：
ADRIANA WEINBERG
金额：
$ 24.38万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10356601
关键词：
Address Affect Aftercare Age Allogenic Antigen-Presenting Cells Archives Area Biological Assay Cells Chickenpox Color Cryopreservation Flow Cytometry Frequencies HIV HIV Infections Immune Immune response Immunity Immunocompetent Immunologic Markers Immunologics Immunosuppression Incidence Infection Influenza Interferon Type II Interferons International Maternal Pediatric Adolescent AIDS Clinical Trials Longevity Low income Malaria Measures Mediating Memory Mononuclear Morbidity - disease rate Mycobacterium tuberculosis Natural Immunity Participant Persons Phase Population Postpartum Period Postpartum Women Pregnancy Pregnant Women Preventive therapy Prophylactic treatment Randomized Regulatory T-Lymphocyte Safety Sampling Sterility T-Lymphocyte Testing Time Training Tuberculosis Tuberculosis Vaccines Vaccination Woman active method adaptive immunity antenatal arm cytotoxic double-blind placebo controlled trial in vivo isoniazid mortality novel novel vaccines pathogen peripheral blood prevent prophylactic reproductive response transcriptome sequencing treatment effect tuberculosis treatment vaccine development young adult

项目摘要

Tuberculosis (TB) is the most important cause of morbidity and mortality among people with HIV in low-income settings. Isoniazid prophylactic therapy (IPT) is currently recommended for people with HIV in areas of high TB endemicity and in those with evidence of latent TB infection (LTBI+) in nonendemic areas. TB predominantly affects young adults, including women of reproductive age. Unlike other infections with intracellular pathogens, which carry highest morbidity during pregnancy and first 2 weeks postpartum, the incidence of active TB infections (ATBI) does not increase during pregnancy, which is surprising in view of the significant loss of M. tuberculosis (Mtb)-specific Th1 responses measured by interferon gamma release assays (IGRA) during pregnancy. The loss of IGRA responses during pregnancy is likely due to the increased frequency of regulatory T cells (Treg), which probably also account for the increased morbidity of influenza, varicella and malaria during pregnancy. We hypothesized that Mtb-specific trained immunity and memory responses (Tmem) are maintained during pregnancy, while Th1 and Th17 effector responses (Teff) decrease and Treg increase. We will address this hypothesis in AIM 1 using peripheral blood mononuclear (PBMC) archived in IMPAACT P1078, which randomized pregnant women with HIV to initiate INH antepartum (AP) or postpartum (PP). AIM 1. To evaluate the effect of pregnancy on trained immunity, Th1, Th17 and Treg responses to Mtb. Subaim 1a. To compare trained immunity, Th1, Th17 and Treg responses to Mtb between AP and PP. Hypothesis: Th1 and Th17 effector responses to Mtb are lower, Treg are higher, and Tmem and trained immunity do not change from AP to PP. We will use 40-color spectral flow cytometry and RNAseq on samples collected at study entry and at 12 weeks PP from women who started IPT at 12 weeks PP. Subaim 1b. To evaluate the relationship of responses to Mtb with pregnancy-induced circulating Treg. Hypothesis: Increased frequency of circulating Treg is associated with decreased Teff responses to Mtb during pregnancy. Other potential associations will be examined for the first time to generate new hypotheses. We will measure the frequency of circulating Treg AP and correlate them with Teff and other responses to Mtb. AIM 2 will evaluate the effect of IPT on Mtb-specific Th1 and Th17 responses and trained immunity. Th1 Teff have been shown to decrease after treatment of ATBI or IPT in people without HIV. This is probably due to decreased antigenic stimulation of Th1 Teff due to elimination of Mtb replication. There is a dearth of information on the effect of treatment on Mtb-specific immunity in people with HIV. However, this information is very important due to the increased loss of Mtb-specific T cells in the context of HIV infection. Using PBMC collected in P1078, we will test the hypothesis that IPT is associated with a decrease in Mtb-specific Th1 and Th17 cells, but it does not affect trained immunity.

结核病（TB）是低收入患者发病率和死亡率的最重要原因设置。目前，建议在高结核病地区的艾滋病毒患者使用异烟肼预防治疗（IPT）在非流行区域中具有潜在结核病感染（LTBI+）证据的人。结核病主要是影响年轻人，包括生殖年龄的妇女。与细胞内病原体的其他感染不同，在怀孕期间和产后最初2周的发病率最高，活性结核病的发生率感染（ATBI）在怀孕期间不会增加，这是M.的重大损失。结核病（MTB） - 特异性TH1反应在干扰素伽马释放分析（IGRA）期间测量怀孕。怀孕期间IGRA反应的丧失可能是由于调节的频率增加 T细胞（Treg），这也可能解释了流感，水痘和疟疾的发病率增加怀孕期间。我们假设MTB特异性训练的免疫力和记忆反应（TMEM）在怀孕期间保持维持，而Th1和Th17效应子响应（TEFF）降低和Treg 增加。我们将使用外周血单核（PBMC）在AIM 1中解决此假设 Inmaact P1078，艾滋病毒随机孕妇启动INH Antpartum（AP）或产后（pp）。目的1。为了评估怀孕对受过训练的免疫力的影响，Th1，Th17和Treg对MTB的反应。 Subaim 1A。为了比较受过训练的免疫力，Th1，Th17和Treg对AP和PP之间的MTB反应。假设：Th1和Th17对MTB的效应子响应较低，Treg较高，TMEM和训练有素免疫力不会从AP变为PP。我们将在研究入口和12周时收集的样品上使用40色光流式细胞仪和RNASEQ PP的PP在第12周开始IPT的女性中。 Subaim 1B。评估对MTB的反应与怀孕引起的循环Treg的关系。假设：循环Treg的频率增加与TEFF对MTB的反应减少有关怀孕期间。将首次检查其他潜在关联以生成新的假设。我们将测量循环Treg AP的频率，并将其与TEFF和对MTB的其他响应相关联。 AIM 2将评估IPT对MTB特异性TH1和TH17响应以及训练的免疫力的影响。 Th1 Teff 已显示在没有艾滋病毒的人治疗ATBI或IPT后减少。这可能是由于由于消除MTB复制而导致TH1 TEFF的抗原刺激减少。缺乏有关治疗对艾滋病毒患者MTB特异性免疫力的影响的信息。但是，此信息是由于在HIV感染的背景下，MTB特异性T细胞的损失增加，非常重要。使用PBMC 在P1078中收集，我们将测试IPT与MTB特异性降低有关的假设 Th1和Th17细胞，但不会影响受过训练的免疫力。