Understanding the immune response changes to clinical interventions for Epstein-Barr virus infection prior to lymphoma development in children after organ transplants (UNEARTH)

了解器官移植后儿童淋巴瘤发展之前针对 Epstein-Barr 病毒感染的临床干预的免疫反应变化（UNEARTH）

• 批准号: 10755205
• 负责人: Vikas R. Dharnidharka
• 金额: $ 98.72万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10755205
• 关键词: Abdomen; Activities of Daily Living; Address; Adult; Allografting; Biological Assay; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Chest; Child; Childhood; Chronic; Clinical; Communicable Diseases; Complication; DNA; Data; Detection; Development; Elements; Epstein-Barr Virus Infections; Epstein-Barr Virus-Related Malignant Neoplasm; Evaluation; Exposure to; Flow Cytometry; Functional disorder; Generations; Goals; Heart; Hodgkin Disease; Human; Human Herpesvirus 4; Immune; Immune response; Immunocompetent; Immunocompromised Host; Immunologics; Immunology; Immunosuppression; Immunotherapy; Individual; Inflammatory; Intervention; Intestines; Kidney; Knowledge; Liver; Lung; Lymphoma; Lymphoproliferative Disorders; Malignant - descriptor; Memory; NK Cell Activation; Natural Killer Cells; Non-Hodgkin' s Lymphoma; Normal Statistical Distribution; Nucleic Acid Amplification Tests; Oncology; Organ Transplantation; Outcome; Pathway interactions; Patients; Pediatric Hospitals; Phase; Phenotype; Plasma; Population; Primary Infection; Prospective cohort; Publishing; Recovery; Sampling; Solid; Standardization; T cell therapy; T memory cell; T-Lymphocyte; Time; Transplant Recipients; Viral; Viral Load result; Viral load measurement; Virus; Virus Replication; Whole Blood; chemokine; co-infection; cytokine; exhaust; exhaustion; experimental study; functional status; high risk; immune function; member; organ transplant recipient; patient subsets; peripheral blood; post-transplant; prevent; programs; prospective; receptor; response; rituximab; translational approach; transplant centers; tumorigenesis; viral DNA; young adult

Abstract/Summary Among the Epstein-Barr virus associated cancers is post-transplant lymphoproliferative disease (PTLD), a rare but major complication of pediatric solid organ transplants (SOT). Many children are EBV-seronegative at time of SOT, leading to primary EBV infection from the allograft under intense immunosuppression, and a higher chance of a chronic high viral load (CHVL) state or PTLD. Longitudinal peripheral blood EBV DNA nucleic acid testing (NAT) has not improved the individual prediction of PTLD occurrence, likely due to variable SOT recipient immune responses. Further, these patients receive clinical interventions for EBV DNAemia, with incomplete responses for unknown reasons. Our team of SOT, infectious disease and immunology professionals will bring new and complimentary expertise to close these knowledge gaps. We will perform longitudinal T and NK cell immune function assays in conjunction with local and central EBV and anellovirus NAT in 1390 samples across 5 time points in the first year after 278 SOT (kidney, liver, heart, lung or intestine) at 3 major children's hospitals. We will accomplish the following Specific Aims, comparing thoracic and abdominal SOT recipients with primary EBV infection or CHVL state: 1. Assess the prospective phenotypic and functional features of T cell “exhaustion” and correlate with EBV infection outcomes and NK cell profile. Hypothesis: SOT recipients' that develop CHVL state display distinct phenotypic memory differentiation and exhausted CD8+ and CD4+ T cell profiles that are regulated by distinct inflammatory circuits. We will accomplish this aim by performing multi- spectral flow cytometry to characterize T cell phenotype and function, as well as Meso Scale Discovery platform to assess distinct viral control-relevant plasma cytokines/chemokines, during the phases of initial replication, expansion, progression, CHVL or recovery states. 2. To prospectively define the number, phenotype, and functional status of NK cells, and correlate with EBV infection outcomes. Hypothesis: NK cell activation will coincide with primary infection, and will correlate positively with clearance vs. negatively with persistent EBV replication. NK cell dysfunction will develop in patients with CHVL, who are at highest risk of PTLD. We will leverage our established multi-spectral flow cytometry panel and analyze patients with primary EBV infection after SOT and answer questions related to the activation status, NK receptor repertoire, and functional capacity. 3. Determine the association of peripheral blood torquetenovirus (TTV) DNA loads to EBV outcomes, T and NK cell profiles. Hypothesis: TTV loads reduce with clinical reductions in immunosuppression and predict EBV clearance. We will accomplish this aim using longitudinal whole blood NAT assays for both viruses at common time points, performed centrally to minimize lab variability. By study end, we will know the T and NK immune responses to EBV across multiple clinical situations. We expect to find key immune mechanisms that will predict poor or delayed EBV clearance despite clinical interventions, which may lead to new translational immunotherapy approaches to prevent PTLD, or inform EBV oncogenesis in other populations.

摘要/摘要 在爱泼斯坦 - 巴尔病毒相关的癌症中，是移植后淋巴增生性疾病（PTLD），这是一种罕见的 但是小儿固体器官移植（SOT）的主要并发症。许多孩子的时间是EBV副词 SOT，导致在强烈的免疫抑制下引起同种异体移植的主要EBV感染，并且较高 慢性高病毒负荷（CHVL）状态或PTLD的机会。纵向外周血EBV DNA核酸 测试（NAT）没有改善PTLD发生的个体预测，这可能是由于可变的SOT接收者 免疫反应。此外，这些患者接受了EBV DNAEMIA的临床干预措施，但不完整 出于未知原因的响应。我们的SOT，传染病和免疫学专业人员团队将带来 新的和免费的专业知识来缩小这些知识差距。我们将执行纵向T和NK单元 免疫功能分析与局部和中央EBV和Anellovirus NAT结合1390样品 在3家主要儿童医院的278个SOT（肾脏，肝脏，心脏，肺或肠道）的第一年中，第一年的5个时间点。 我们将完成以下特定目的，将胸腔和腹部SOT接受者与主要目标进行比较 EBV感染或CHVL状态：1。评估T细胞的前瞻性表型和功能特征 “疲惫”并与EBV感染结果和NK细胞谱相关。假设：SOT接收者 开发CHVL状态显示出不同的表型记忆分化以及耗尽的CD8+和CD4+ T 受不同炎症回路调节的细胞谱。我们将通过执行多种多样来实现这一目标 光谱流式细胞仪表征T细胞表型和功能以及中尺度发现平台 在初始复制的阶段，评估不同病毒控制的血浆细胞因子/趋化因子/趋化因子， 扩展，进展，CHVL或恢复状态。 2。前瞻性定义数量，表型和 NK细胞的功能状态，并与EBV感染结果相关。假设：NK细胞激活 将与原发性感染一致，并将与清除与否定性与持续的EBV呈正相关 复制。 CHVL患者的NK细胞功能障碍将发展为PTLD风险最高的患者。我们将 利用我们已建立的多光谱流式细胞仪面板并分析原发性EBV感染的患者 SOT并回答与激活状态，NK受体库和功能能力有关的问题。 3。确定外周血turquetenovirus（TTV）DNA载荷与EBV结局的关联，t 和NK细胞曲线。假设：随着免疫抑制的临床减少，TTV负载减少并预测 EBV间隙。我们将使用两种病毒的纵向全血NAT分析来实现这一目标 普通时间点，集中执行以最大程度地减少实验室变异性。按研究端，我们将知道T和NK 在多种临床情况下对EBV的免疫反应。我们希望找到关键的免疫机制 将预测EBV清除较差或延迟所需的临床干预措施，这可能会导致新的翻译 免疫疗法预防PTLD或告知其他人群中EBV的肿瘤发生的方法。