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/总结 与 Epstein-Barr 病毒相关的癌症包括移植后淋巴组织增生性疾病 (PTLD)，这是一种罕见的疾病 但这是儿科实体器官移植 (SOT) 的主要并发症，许多儿童有时 EB 病毒血清呈阴性。 SOT，导致在强烈的免疫抑制下同种异体移植物发生原发性 EBV 感染，并且更高 慢性高病毒载量 (CHVL) 状态或 PTLD 纵向外周血 EBV DNA 核酸的可能性。 测试（NAT）并没有改善对 PTLD 发生的个体预测，可能是由于 SOT 接受者的可变性 此外，这些患者接受 EBV DNA 血症的临床干预，但不完全。 我们的 SOT、传染病和免疫学专业团队将带来未知原因的响应。 我们将进行纵向 T 和 NK 细胞研究，以填补这些知识空白。 对 1390 个样本中的局部和中枢 EBV 以及指环病毒 NAT 进行免疫功能测定 在3家主要儿童医院进行278次SOT（肾、肝、心、肺或肠）后第一年的5个时间点。 我们将实现以下具体目标，将胸部和腹部 SOT 接受者与原发性接受者进行比较 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 细胞特征相关 假设：SOT 接受者的。 形成 CHVL 状态的细胞表现出明显的表型记忆分化和耗尽的 CD8+ 和 CD4+ T 我们将通过执行多种方法来实现这一目标。 用于表征 T 细胞表型和功能的光谱流式细胞术以及 Meso Scale Discovery 平台 在初始复制阶段评估不同的病毒控制相关血浆细胞因子/趋化因子， 扩展、进展、CHVL 或恢复状态 2. 前瞻性地定义数量、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。 与原发感染同时发生，并且与清除率呈正相关，与持续性 EBV 呈负相关 CHVL 患者会出现 NK 细胞复制功能障碍，他们患 PTLD 的风险最高。 利用我们建立的多光谱流式细胞仪组来分析原发性 EBV 感染患者 SOT 后并回答与激活状态、NK 受体库和功能能力相关的问题。 3. 确定外周血扭矩病毒 (TTV) DNA 载量与 EBV 结果的关联，T 假设：TTV 负荷随着临床免疫抑制的减少而减少，并预测。 我们将使用两种病毒的全血 NAT 检测来实现这一目标。 共同时间点，集中执行以最大限度地减少实验室变异性。在研究结束时，我们将了解 T 和 NK。 我们期望找到针对多种临床情况的 EBV 免疫反应。 尽管进行了临床干预，仍将预测 EBV 清除率较差或延迟，这可能会导致新的转化 免疫治疗方法可预防 PTLD，或告知其他人群 EBV 肿瘤发生。