Chronic High EBV load and risk of PTLD in Pediatric Heart Transplant Patients

小儿心脏移植患者的慢性高 EBV 载量和 PTLD 风险

• 批准号: 8258732
• 负责人: DIANA M METES
• 金额: $ 37.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-15 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8258732
• 关键词: B-Lymphocytes; Biological Markers; Burkitt Lymphoma; CD28 gene; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Cessation of life; Chest; Child; Childhood; Chronic; Clinic; Data; Development; Diagnosis; Diffuse; Epstein-Barr Virus Infections; Family; Family member; Future; Goals; Heart Transplantation; Hodgkin Disease; Human Herpesvirus 4; Immunity; Immunologics; Immunosuppression; Incidence; Life; Ligands; Lymphoma; Lymphoproliferative Disorders; Malignant Neoplasms; Molecular; Monitor; Onset of illness; Organ Transplantation; Outcome; Pathway interactions; Patients; Phenotype; Regulation; Research; Risk; Solid; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic Agents; Therapeutic Intervention; Transplant Recipients; Transplantation; Validation; Viral Load result; Viral load measurement; antigen challenge; base; cytokine; exhaust; exhaustion; high risk; improved; novel; novel therapeutic intervention; novel therapeutics; peripheral blood; prevent; prognostic; programs; public health relevance; receptor; selective expression

DESCRIPTION (provided by applicant): Post-transplantation lymphoproliferative disorders (PTLD) are life-threatening complications of solid organ transplantation (SOTx), caused by Epstein Barr Virus (EBV) infections and the use of chronic non-specific immunosuppression (IS). The incidence of PTLD in patients who are EBV seronegative prior to transplantation, mostly pediatric patients, is as high as 25%. The onset of the disease is usually preceded by an elevated EBV load in the peripheral blood which is highly sensitive but not specific for the diagnosis of PTLD. Our group and others have shown that routine long-term post-Tx viral load monitoring identifies a group of children who carry persistent very high viral loads for months to years after primary post-Tx EBV infection. We recently showed that these chronic high EBV load asymptomatic carriers have a 45% rate of progression to late-onset PTLD, including diffuse large B cell, Hodgkin's and Burkitt's lymphomas. To date, there is no clear understanding of how these viral loads are occurring or maintained, nor how we can predict which patients will develop chronic high viral loads and progress towards PTLD/lymphoma. Here we propose to elucidate the immunologic mechanisms responsible for this phenomenon and define novel prognostic "immunologic signatures" that can be used in the clinic to identify patients at risk of progression towards PTLD. In the first Aim we will assess the phenotypic and functional features of "exhausted" EBV-specific CD8+ and CD4+ T cells in pediatric transplant patients carrying chronic high EBV load, as compared to low or absent EBV load carriers. In Aim 2 we will characterize the co-regulation of "exhausted" EBV-specific CD8+ T cells by inhibitory receptors and by "helper" ? chain family cytokines in chronic high EBV load pediatric transplant patients, as compared to low or absent EBV load carriers. In Aim 3 we will investigate intrinsic molecular mechanisms underlying exhaustion of EBV- specific CD8+ T cells in pediatric transplant patients carrying chronic high EBV load, and compare results to those from low or absent EBV load carriers. These studies will provide a rational basis for future implementation of cellular monitoring in the clinic to identify exhausted EBV-specific CD8+ T cells and the risk of progression to PTLD. These studies could also provide support for early therapeutic intervention (lowering IS) and for the development of novel therapeutic approaches to reverse CD8+ T cell exhaustion and improve outcomes in pediatric Tx patients. PUBLIC HEALTH RELEVANCE: This research will improve the understanding of immunologic and molecular mechanisms causing for certain high chronic EBV load pediatric HTx patients to display impaired EBV-specific immunity, and to be at higher risk to progress towards PTLD. Our goal is not only to identify useful immunologic biomarkers that might help monitor and predict which patients are at risk of progression towards malignancy, but also to reveal the molecular pathways that may be targeted with novel therapeutic agents to prevent or improve the outcomes of PTLD in the pediatric transplant setting.

描述（由申请人提供）：移植后淋巴增殖性疾病（PTLD）是实体器官移植（SOTx）的危及生命的并发症，由EB病毒（EBV）感染和使用慢性非特异性免疫抑制（IS）引起。移植前 EBV 血清阴性的患者（主要是儿童患者）中 PTLD 的发生率高达 25%。疾病发作之前，外周血中 EBV 载量通常会升高，这对 PTLD 的诊断高度敏感，但不具有特异性。我们的小组和其他人已经表明，常规的长期 Tx 后病毒载量监测可以识别出一组在初次 Tx EBV 感染后数月至数年内持续携带极高病毒载量的儿童。我们最近发现，这些慢性高 EBV 载量无症状携带者有 45% 的几率进展为迟发性 PTLD，包括弥漫性大 B 细胞淋巴瘤、霍奇金淋巴瘤和伯基特淋巴瘤。迄今为止，尚不清楚这些病毒载量是如何发生或维持的，也不清楚我们如何预测哪些患者将出现慢性高病毒载量并进展为 PTLD/淋巴瘤。在这里，我们建议阐明造成这种现象的免疫机制，并定义新的预后“免疫学特征”，可用于临床识别有进展为 PTLD 风险的患者。在第一个目标中，我们将评估携带慢性高 EBV 载量的儿科移植患者与低或不存在 EBV 载量的儿童移植患者中“耗尽”的 EBV 特异性 CD8+ 和 CD4+ T 细胞的表型和功能特征。在目标 2 中，我们将描述抑制性受体和“辅助细胞”对“耗尽”的 EBV 特异性 CD8+ T 细胞的共同调节作用？与低或无 EBV 负载携带者相比，慢性高 EBV 负载儿科移植患者的链家族细胞因子。在目标 3 中，我们将研究携带慢性高 EBV 负载的儿科移植患者 EBV 特异性 CD8+ T 细胞耗竭的内在分子机制，并将结果与​​低或无 EBV 负载携带者的结果进行比较。这些研究将为未来在临床上实施细胞监测提供合理的基础，以识别耗尽的 EBV 特异性 CD8+ T 细胞和进展为 PTLD 的风险。这些研究还可以为早期治疗干预（降低 IS）以及开发新的治疗方法来逆转 CD8+ T 细胞耗竭并改善儿科 Tx 患者的预后提供支持。 公共健康相关性：这项研究将增进对免疫学和分子机制的理解，这些机制导致某些慢性 EBV 负荷较高的儿科 HTx 患者表现出 EBV 特异性免疫受损，并且进展为 PTLD 的风险更高。我们的目标不仅是确定有用的免疫生物标志物，帮助监测和预测哪些患者有进展为恶性肿瘤的风险，而且还揭示新治疗药物可能针对的分子途径，以预防或改善儿科移植环境中 PTLD 的结果。