PTLD: cytokine production and gene polymorphisms

描述（由申请人提供）： 移植后淋巴增生性疾病（PTLD）是一种严重的并发症，通常与免疫抑制治疗（IST）后EBV+ B细胞克隆的不受控制的扩增有关。尽管患者年龄、同种异体移植物类型和IST强度是影响PTLD发生的危险因素，但为什么PTLD在某些移植受者中发生而在其他受者中不发生仍不清楚。其他因素，包括宿主的遗传背景，可能在PTLD中发挥重要作用。强有力的证据表明，EBV反应性细胞免疫和TH-1细胞因子如干扰素γ（IFN-γ）是预防EBV再活化和控制PTLD的重要因素。细胞因子基因的多态性可以影响细胞因子的分泌和功能，从而为研究细胞因子基因中已知的序列多态性作为PTLD发展的可能风险因素提供了令人信服的理论基础。我们假设移植患者免疫能力固有的遗传多态性是决定PTLD风险的一个因素。自发性人EBV+淋巴增生性疾病（EBV-LPD）的临床前SCID小鼠（hu-PBL-SCID）模型和少量PTLD患者中的初步数据表明，IFN-γ基因碱基+874处的A/T单核苷酸多态性与hu-PBL-SCID小鼠中PTLD和EBV-LPD的发展相关。为了证实这些发现，我们将进行一项多中心回顾性研究，以评估PTLD患者中A/T +874 IFN-g基因型的患病率，并将其与匹配的非PTLD移植对照进行比较（具体目标1）。我们还将检验以下假设：与T/T基因型相比，A/A IFN-γ基因型的PBL响应于自体EBV LCL刺激具有较少的IFN-γ产生CD 8+细胞和/或较低的总体IFN-γ产生（具体目标2）。我们的团队由A博士组成。VanBuskirk（免疫学家，细胞因子基因分型），P. Porcu（成人PTLD/淋巴瘤临床医生和研究人员），T. Gross（儿科PTLD/淋巴瘤临床医生和研究人员），A. Ferketich（流行病学和统计学）和R. Baiocchi（专门研究PTLD和hu-PBL-SCID小鼠的医生科学家）。能够识别PTLD高风险患者将在治疗和预防策略方面非常有益。我们的总体目标是利用这些数据作为R 01提案的跳板，以研究PTLD的分子流行病学，并在PTLD患者中进行前瞻性治疗临床试验。

DESCRIPTION (provided by applicant): Post-transplant lymphoproliferative disorder (PTLD) is a serious complication typically associated with uncontrolled expansion of EBV+ B-cell clones following institution of immunosuppressive therapy (IST). Why PTLD develops in some transplant recipients but not in others remains unclear, although patient age, allograft type, and intensity of IST are implicated as risk factors. Additional factors, including the genetic background of the host, are likely to play an important role in PTLD. Strong evidence implicates EBV-reactive cellular immunity and TH-1 cytokines like interferon gamma (IFN-gamma) as important factors to prevent EBV reactivation and to control PTLD. Poly-morphisms in cytokine genes can affect cytokine secretion and function, thus providing a compelling rationale to study known sequence polymorphisms in cytokine genes as possible risk factors for the development of PTLD. We hypothesize that genetic polymorphisms inherent to the immune capacity of transplant patients is a contributing factor in determining risk of PTLD. Preliminary data in a preclinical SCID mouse (hu-PBL-SCID) model of spontaneous human EBV+ lymphoproliferative disorder (EBV-LPD) and in a small number of PTLD patients suggest that a A/T single nucleotide polymorphism at base +874 of the IFN-g gene is linked to the development of PTLD and EBV-LPD in hu-PBL-SCID mice. To confirm these findings, we will perform a multi-center, retrospective study to assess the prevalence of the A/T +874 IFN-g genotype in PTLD patients, and compare it to that of matched, non-PTLD transplant controls (Specific Aim 1). We will also test the hypothesis that PBL of the A/A IFN-gamma genotype have fewer IFN-gamma producing CD8+ cells and/or lower overall IFN-g production in response to autologous EBV LCL stimulation, compared to the T/T genotype (Specific Aim 2). Our team consists of Drs. A. VanBuskirk (immunologist, cytokine genotyping), P. Porcu (adult PTLD/lymphoma clinician and researcher), T. Gross (pediatric PTLD/lymphoma clinician and researcher), A. Ferketich (epidemiology and statistics) and R. Baiocchi (physician scientist specializing in PTLD and hu-PBL-SCID mouse). Being able to identify patients at high risk for PTLD would be very beneficial in terms of treatment and prevention strategies. Our overall goal is to use this data as a springboard for R01 proposals to study the molecular epidemiology of PTLD and to perform prospective therapeutic clinical trials in PTLD patients.