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

描述（由申请人提供）：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）引起。移植前EBV血清阴性的患者，主要是儿科患者，PTLD的发生率高达25%。该疾病的发病通常先于外周血中EBV载量升高，这对PTLD的诊断高度敏感，但不是特异性的。我们的研究小组和其他研究表明，常规的长期tx后病毒载量监测可以识别出一组在原发性tx后EBV感染后数月至数年内持续携带非常高病毒载量的儿童。我们最近发现，这些慢性高EBV载量无症状携带者有45%的进展率为晚发性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，对于这些病毒载量是如何发生或维持的，以及我们如何预测哪些患者会发展为慢性高病毒载量并进展为PTLD/淋巴瘤，还没有明确的认识。在这里，我们建议阐明导致这一现象的免疫机制，并定义新的预后“免疫特征”，这些特征可以在临床中用于识别有PTLD进展风险的患者。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中“耗尽”EBV特异性CD8+和CD4+ T细胞的表型和功能特征，与低或无EBV载量携带者相比。在目标2中，我们将描述抑制受体和“辅助”受体对“耗尽”ebv特异性CD8+ T细胞的共同调节。链家族细胞因子在慢性高EBV载量儿童移植患者中的作用，与低或无EBV载量携带者相比。在Aim 3中，我们将研究携带慢性高EBV载量的儿童移植患者EBV特异性CD8+ T细胞耗竭的内在分子机制，并将结果与低EBV载量或无EBV载量携带者的结果进行比较。这些研究将为未来在临床中实施细胞监测提供合理的基础，以确定耗尽的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）和开发新的治疗方法提供支持，以逆转CD8+ T细胞衰竭，改善小儿Tx患者的预后。

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.