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

基本信息

批准号：
8452060
负责人：
DIANA M METES
金额：
$ 35.36万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-15 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8452060
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

项目摘要

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.

描述（由申请人提供）：移植后淋巴增生性疾病（PTLD）是由爱泼斯坦Barr病毒（EBV）感染引起的固体器官移植（SOTX）的生命并发症，并且使用了慢性非特异性非特异性免疫抑制（IS）。在移植前具有EBV血清负格的患者PTLD的发生率（主要是儿科患者）高达25％。该疾病的发作通常在周围血液中的EBV负荷升高之前，该血液高度敏感，但对PTLD的诊断不具体。我们的小组和其他人表明，常规的长期TX病毒载荷监测识别一组儿童在初次TX EBV感染后几个月至几年中持续持续的非常高的病毒载荷。我们最近表明，这些慢性高EBV载荷无症状载体的发展速率为45％，包括弥漫性大B细胞，霍奇金和伯基特的淋巴瘤。迄今为止，尚无清楚地了解这些病毒负荷是如何发生或维持的，也没有我们如何预测哪些患者会发展出慢性高病毒载量并朝PTLD/淋巴瘤发展。在这里，我们建议阐明负责这种现象的免疫机制，并定义可在诊所中使用的新型预后“免疫特征”，以识别有前进风险向PTLD进展的患者。在第一个目的中，与低或缺乏EBV负载载体相比，我们将评估“耗尽”的EBV特异性CD8+和CD4+ T细胞的表型和功能特征，其携带慢性EBV负荷的儿科移植患者的表型和功能特征。在AIM 2中，我们将通过抑制受体和“助手”来表征“耗尽”的EBV特异性CD8+ T细胞的共同调节？与低或不存在的EBV负载载体相比，慢性EBV负载小儿移植患者中的链家族细胞因子。在AIM 3中，我们将研究带有慢性EBV负载的小儿移植患者中EBV-特异性CD8+ T细胞筋疲力尽的固有分子机制，并将结果与低或缺乏EBV负载载体的结果进行比较。这些研究将为诊所中细胞监测的未来实施提供合理的基础，以鉴定耗尽的EBV特异性CD8+ T细胞和进展到PTLD的风险。这些研究还可以为早期的治疗干预（降低IS）提供支持，并开发了新型治疗方法，以逆转CD8+ T细胞衰竭并改善小儿TX患者的结局。