Epstein Barr Virus Driven Mechanisms of Post Transplant Lymphoproliferative Disease

项目总结/摘要 爱泼斯坦巴尔病毒（EBV）是一种广泛传播的γ疱疹病毒，其在免疫抑制或免疫抑制的情况下， 免疫功能低下的个体可引起严重的、危及生命的B细胞淋巴瘤。实体器官移植 (SOT)这些EBV+ B细胞淋巴瘤是该组中最严重的表现， 移植后淋巴组织增生性疾病（PTLD）。易感 PTLD的因素包括原发性EBV感染、受体B细胞中EBV的再活化和受损的T细胞 由于免疫抑制而产生的免疫力。我们对特定病毒基因如何 在EBV+ PTLD的背景下，是否有助于淋巴瘤的发生，以及是否有特定的改变， 与未发生EBV+ PTLD SOT相比，发生EBV+ PTLD的SOT对EBV的免疫应答。我们之前的工作 研究小组专注于潜伏膜蛋白1（LMP 1），EBV的主要致癌基因，以更好地了解 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，我们证实了 LMP 1中特异性功能获得突变与EBV+ PTLD的发生显著相关。 我们还证明了EBV改变了宿主细胞的microRNA谱，这对存活率有直接影响。 EBV+ B淋巴瘤细胞。在我们之前对之间双向相互作用的创新研究的基础上， EBV和宿主免疫，并使用我们独特的SOT接受者样本生物储存库， EBV+ PTLD和未发生EBV+ PTLD的匹配SOT对照，我们建议定义 病毒遗传多样性对EBV保护性免疫应答的影响。我们假设EB病毒遗传多样性导致 病毒基因功能和免疫识别的改变导致EBV+ PTLD的发病机制。 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 2）确定EBV+ PTLD相关的遗传多样性对宿主细胞功能的影响 3）确定细胞外囊泡和microRNA如何促进EBV的发展。 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，并将揭示新的治疗策略，以防止 以及治疗免疫抑制和免疫受损个体中的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.