Epstein Barr Virus Driven Mechanisms of Post Transplant Lymphoproliferative Disease

EB 病毒驱动的移植后淋巴增殖性疾病的机制

• 批准号: 10755055
• 负责人: Sheri M. Krams
• 金额: $ 62.79万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10755055
• 关键词: Activities of Daily Living; Allografting; B-Cell Lymphomas; B-Lymphocytes; Blood; Cell Proliferation; Cell Survival; Cell physiology; Cells; Characteristics; Custom; Cytometry; Development; Epithelium; Epstein Barr Virus B cell lymphoma; Epstein Barr Virus B lymphoma cell; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Epstein-Barr pathogenesis; FOS gene; Genes; Genetic Variation; Goals; HIV; Herpesviridae; Human Herpesvirus 4; Immune; Immune response; Immunity; Immunocompromised Host; Immunosuppression; Impairment; Individual; Infection; Life; Link; Lymphoid; Lymphomagenesis; Lymphoproliferative Disorders; Lytic Phase; Lytic Virus; MAP Kinase Gene; Malignant Neoplasms; Membrane Proteins; MicroRNAs; Modeling; Molecular; Morbidity - disease rate; Multi-Institutional Clinical Trial; Mutation; NCAM1 gene; Natural Killer Cells; Oncogenes; Organ Transplantation; Pathogenesis; Patients; Peptides; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Plasma; Population; Predisposing Factor; Proliferating; Proteins; Risk; Role; Sampling; Signal Pathway; Solid; T cell response; T-Lymphocyte; Testing; Therapeutic; Transcription Factor AP-1; Transplant Recipients; Variant; Viral; Viral Genes; Viral Pathogenesis; Viral Proteins; Virus; Work; adaptive immune response; antiviral immunity; biobank; cell transformation; extracellular vesicles; gain of function mutation; gene function; genome sequencing; high dimensionality; immunoregulation; immunosuppressed; infected B cell; innovation; mortality; novel; organ transplant recipient; post-transplant; prevent; prospective; response; transforming virus; tumor; virus genetics; whole genome

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.

项目摘要/摘要 爱泼斯坦Barr病毒（EBV）是一种广泛传播的伽马广播病毒，在免疫抑制或 免疫功能低下的个体会导致严重的，威胁生命的B细胞淋巴瘤。在实体器官移植中 （SOT）接受者这些EBV+ B细胞淋巴瘤是该组最严重的表现 异质性淋巴结增生性称为移植后淋巴增生疾病（PTLD）。易感性 PTLD的因素包括原发性EBV感染，受体B细胞中EBV的重新激活以及T细胞受损 免疫抑制引起的免疫力。我们对特定病毒基因的理解有很大的差距 在EBV+ PTLD的背景下有助​​于淋巴作用，以及是否存在特定的改变 与不具有的eBV+ PTLD相比，SOT中对EBV的免疫反应。我们的事先工作 小组专注于EBV的主要癌基因潜伏膜蛋白1（LMP1），以更好地理解 EBV+ PTLD发病机理。在SOT接受者的最近的前瞻性多中心临床试验中，我们证明了 LMP1中功能突变的特定增益与EBV+ PTLD的发展显着相关。 我们还证明了EBV改变了宿主细胞microRNA的轮廓，这对生存有直接影响 EBV+ B淋巴瘤细胞的。基于我们以前对双向相互作用之间的创新研究 EBV和宿主免疫，并使用我们从SOT接收者中的独特样品生物座 EBV+ PTLD和不发展EBV+ PTLD的SOT控件，我们建议定义 病毒遗传多样性对受保护的EBV免疫反应。我们假设EBV遗传多样性导致 对病毒基因功能的改变和免疫识别有助于EBV+ PTLD的发病机理。 为了检验该假设，我们提出以下特定目的：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）确定EBV+ PTLD相关遗传多样性对宿主的影响 对EBV的免疫力和3）确定细胞外蔬菜和microRNA如何促进 EBV+ PTLD。我们预计这些研究将确定由EBV驱动的新机制 B细胞淋巴瘤在PTLD中的发病机理，并将揭示治疗策略的新机会以防止 并治疗免疫抑制和免疫功能低下个体中的EBV+ B细胞淋巴瘤。