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

描述(申请人提供)：移植后淋巴增生性疾病(PTLD)是实体器官移植(SOTx)的危及生命的并发症，由EB病毒(EBV)感染和慢性非特异性免疫抑制(IS)的使用引起。在移植前EBV血清阴性的患者中，PTLD的发生率高达25%，其中大部分是儿科患者。疾病发生前通常会出现外周血中EB病毒载量升高，这对诊断PTLD是高度敏感的，但不是特异性的。我们小组和其他人已经证明，常规的TX后病毒载量长期监测发现了一组儿童，他们在TX后EBV原发感染后持续数月至数年携带非常高的病毒载量。我们最近发现，这些慢性高EBV载量无症状携带者有45%的进展率发展为迟发性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。到目前为止，还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发展为慢性高病毒载量并进展为PTLD/淋巴瘤。在这里，我们建议阐明导致这一现象的免疫学机制，并定义新的预后“免疫学标志”，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EBV载量携带者和无EBV载量携带者相比，“衰竭”的EBV特异性CD8+和CD4+T细胞的表型和功能特征。在目标2中，我们将表征“疲惫的”EBV特异性CD8+T细胞由抑制性受体和“辅助”？慢性EBV载量高的儿科移植患者中的链状家族细胞因子，与EBV载量低或缺失的携带者相比。在目标3中，我们将研究携带慢性高EBV载量的儿科移植患者EBV特异性CD8+T细胞耗竭的内在分子机制，并将结果与低EBV载量携带者或无EBV载量携带者的结果进行比较。这些研究将为将来在临床上实施细胞监测以识别耗竭的EBV特异性CD8+T细胞和进展为PTLD的风险提供合理的基础。这些研究还可以为早期治疗干预(降低IS)和开发新的治疗方法以逆转CD8+T细胞耗竭和改善儿童TX患者的预后提供支持。 公共卫生相关性：这项研究将提高对某些慢性EBV载量较高的儿童HTX患者表现出EBV特异性免疫受损，并处于进展为PTLD的更高风险的免疫学和分子机制的理解。我们的目标不仅是识别有用的免疫生物标记物，帮助监测和预测哪些患者有进展为恶性肿瘤的风险，而且还揭示可能被新型治疗药物靶向的分子途径，以预防或改善儿童移植环境中PTLD的结果。

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.