Epstein Barr Virus Driven Mechanisms of Post Transplant Lymphoproliferative Disease

项目摘要/摘要 爱泼斯坦-巴尔病毒(EBV)是一种广泛传播的伽马疱疹病毒，在免疫抑制或 免疫功能受损的人，会导致严重的、危及生命的B细胞淋巴瘤。在固体器官移植中 (SOT)受者这些EBV+B细胞淋巴瘤是该组最严重的表现 异质性淋巴增殖症称为移植后淋巴增生性疾病(PTLD)。易感 PTLD的因素包括原发的EBV感染、受体B细胞中EBV的重新激活和T细胞受损 由于免疫抑制而产生免疫力。在我们对特定的病毒基因如何 在EBV+PTLD的背景下导致淋巴肿大，以及在 与未发生EBV+PTLD的SOT相比，发生EBV+PTLD的SOT患者对EBV的免疫应答。之前的工作来自我们的 为了更好地了解EBV的主要癌基因，该小组已将重点放在潜伏膜蛋白1(LMP1)上 EBV+PTLD发病机制。在最近一项针对SOT受者的前瞻性多中心临床试验中，我们展示了 LMP1功能突变的特异性增加与EBV+PTLD的发生显著相关。 我们还证明了EBV会改变宿主细胞的microRNA图谱，这对生存有直接影响 EBV+B淋巴瘤细胞。建立在我们之前对双向相互作用的创新性研究基础上 EBV和宿主免疫，并使用我们独特的SOT受者样本生物库 EBV+PTLD和未发展为EBV+PTLD的匹配SOT对照，我们建议定义 EBV保护性免疫应答中的病毒遗传多样性。我们假设EBV基因多样性导致 EBV+PTLD的发病机制可能与病毒基因功能和免疫识别的改变有关。 为了验证这一假设，我们提出了以下具体目标：1)确定PTLD中EBV的遗传多样性 以及对宿主细胞功能的影响2)决定了EBV+PTLD相关的遗传多样性对宿主的影响 对EBV的免疫力和3)确定细胞外小泡和microRNA如何促进 EBV+PTLD。我们预计这些研究将确定EBV驱动的新机制 PTLD中B细胞淋巴瘤的发病机制，将为预防的治疗策略提供新的机会 以及治疗免疫抑制和免疫受损患者的EBV+B细胞淋巴瘤。

PROJECT SUMMARY/ABSTRACT Epstein Barr virus (EBV) is a broadly disseminated gammaherpes virus that, in immunosuppressed or immunocompromised individuals, can cause serious, life-threatening B cell lymphomas. In solid organ transplant (SOT) recipients these EBV+ B cell lymphomas are the most serious manifestation of the group of heterogeneous lymphoproliferations termed post-transplant lymphoproliferative disease (PTLD). Predisposing factors for PTLD include primary EBV infection, reactivation of EBV in recipient B cells, and impaired T cell immunity due to immunosuppression. There are major gaps in our understanding of how specific viral genes contribute to lymphomagenesis in the context of EBV+ PTLD and whether there are specific alterations in the immune response to EBV in SOT that develop EBV+ PTLD compared to those that do not. Prior work from our group has focused on latent membrane protein 1 (LMP1), the major oncogene of EBV, to better understand EBV+ PTLD pathogenesis. In a recent prospective, multicenter clinical trial in SOT recipients we demonstrated that specific gain of function mutations in LMP1 significantly correlate with the development of EBV+ PTLD. We’ve also demonstrated that EBV alters the host cell microRNA profile and that this has direct effects on survival of EBV+ B lymphoma cells. Building on our previous innovative studies of the bidirectional interactions between EBV and host immunity, and using our unique Biorepository of samples from SOT recipients that developed EBV+ PTLD and matched SOT controls that did not develop EBV+ PTLD, we propose to define the impact of viral genetic diversity on protective immune responses to EBV. We hypothesize that EBV genetic diversity leads to alterations in viral gene function and immune recognition that contribute to the pathogenesis of EBV+ PTLD. To test this hypothesis we propose the following Specific Aims:1) Determine the genetic diversity of EBV in PTLD and the impact on host cell function 2) Determine the effect of EBV+ PTLD-associated genetic diversity on host immunity to EBV and 3) Determine how extracellular vesicles and microRNA contribute to the development of EBV+ PTLD. We anticipate these studies will identify novel mechanisms underlying the EBV-driven pathogenesis of B cell lymphomas in PTLD and will reveal new opportunities for therapeutic strategies to prevent and treat EBV+ B cell lymphomas in immunosuppressed and immunocompromised individuals.