PREVENTION AND ANTIVIRAL TREATMENT FOR EBV LYMPHOMAGENESIS

描述(由申请人提供)： 在EB病毒被发现50年后，仍然没有有效的治疗方法来干预任何EBV感染的发病机制，包括那些导致获得性或先天性免疫缺陷患者发生致命B细胞淋巴瘤的感染。移植了能产生人类B、T和NK细胞的人造血干细胞和重建的人类免疫系统的人源化小鼠模型的快速发展，现在已经提供了适合于治疗人类EBV疾病的小动物模型。人源化NOD/SCID？C-/-(NSG)小鼠感染EBV后，从病毒复制的亚临床阶段发展为多克隆EBV B细胞淋巴增殖性疾病，最终发展为致死性CD20+、EBV EBER阳性的大细胞单克隆性B细胞淋巴瘤。在一个目标上，我们将感染由单一捐赠者的干细胞重组的NSG小鼠的EBV队列，进行对照试验，旨在测试抗EBV药物Maribavir(MBV)单独或与Rituximab一起使用是否可以流产或延缓疾病的可逆多克隆淋巴增殖期，当存在病毒细胞间传播时，到不可逆转的单克隆性淋巴瘤。免疫球蛋白基因重排和EBV基因组末端探针分析将区分多克隆和单克隆期。治疗组和安慰剂组之间比较的基础将是用Kaplan-Meier生存曲线分析动物的存活率并进行统计学意义分析。这些研究将以盲法进行，并将提供第一批前瞻性、安慰剂对照试验，以确定抗病毒药物是否单独或与无毒抗肿瘤药物利妥昔单抗一起影响EBV恶性肿瘤的进程。这一结果可能为这些最终致命的移植后淋巴瘤提供无毒替代疗法的基础。结果也可能对EB病毒载量上升的艾滋病患者有用，这可能预示着B细胞淋巴瘤的发生。

DESCRIPTION (provided by applicant): Fifty years after discovery of Epstein - Barr virus there is still no effective treatment to interrpt pathogenesis of any EBV infections including those that result in fatal B-cell lymphomas in patients with acquired or inborn immunodeficiency. Rapid development of humanized mice models engrafted with transplanted human hematopoietic stem cells that generate human B, T, and NK cells and a reconstituted human immune system have now provided small animal models suitable for treatment of studies human EBV disease. Infection of humanized NOD/SCID ?C-/- (NSG) mice with EBV produces infection that proceeds from a subclinical phase during which virus is replicated to development of polyclonal EBV B-cell lymphoproliferative disease and ultimately lethal CD20+, EBV EBER-positive, large-cell monoclonal B-cell lymphomas. In a single Aim we will infect with EBV cohorts of NSG mice reconstituted with stem cells from single donors for controlled trials designed to test whether an anti-EBV drug, Maribavir (MBV) alone or together with Rituximab can abort or retard progression from the reversible polyclonal lymphoproliferative phase of disease, when there is cell-to-cell transmission of virus, to irreversible monoclonal lymphoma. Polyclonal and monoclonal phases will be distinguished both by IgH gene rearrangements and EBV genomic terminal probe analyses. Basis for comparisons between treatment and placebo groups will be survival of animals analyzed with Kaplan-Meier survival curves and for statistical significance. These studies will be conducted in blinded fashion and will provide the first prospective, placebo-controlled trials of whether an antiviral drug, either alone or together with the nontoxic anti-tumor agent Rituximab, can affect the course of an EBV malignancy. Results may provide the basis for a nontoxic alternative therapy for these ultimately lethal post-transplant lymphomas. Results may also be of use in patients with AIDS who have rising EBV viral loads that may herald genesis of B-cell lymphomas.