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.

项目概要/摘要 EB 病毒 (EBV) 是一种广泛传播的伽马疱疹病毒，在免疫抑制或 免疫功能低下的个体，在实体器官移植中可能会导致严重的、危及生命的 B 细胞淋巴瘤。 (SOT) 受者，这些 EBV+ B 细胞淋巴瘤是一组最严重的表现 异质性淋巴组织增生，称为移植后淋巴组织增生性疾病（PTLD）。 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发挥作用的理解存在重大差距。 在 EBV+ PTLD 的背景下对淋巴瘤发生的影响以及是否存在特定的改变 与我们之前的工作相比，发生 EBV+ PTLD 的 SOT 对 EBV 的免疫反应。 研究小组将重点放在潜伏膜蛋白 1 (LMP1)（EBV 的主要癌基因）上，以更好地了解 在最近一项针对 SOT 接受者的前瞻性、多中心临床试验中，我们证明了 EBV+ PTLD 发病机制。 LMP1 的特定功能获得突变与 EBV+ PTLD 的发展显着相关。 我们还证明 EBV 会改变宿主细胞的 microRNA 谱，这对生存有直接影响 基于我们之前对 EBV+ B 淋巴瘤细胞之间双向相互作用的创新研究。 EBV 和宿主免疫，并使用我们独特的 SOT 接受者样本生物存储库开发 EBV+ PTLD 和未开发 EBV+ PTLD 的匹配 SOT 对照，我们建议定义以下影响： 病毒遗传多样性对 EBV 保护性免疫反应的影响 我们认为 EBV 遗传多样性领先。 病毒基因功能和免疫识别的改变导致 EBV+ PTLD 的发病机制。 为了检验这一假设，我们提出以下具体目标：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) 确定 EBV+ PTLD 相关遗传多样性对宿主的影响 对 EBV 的免疫力以及 3) 确定细胞外囊泡和 microRNA 如何促进 EBV 的发展 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，并将揭示预防治疗策略的新机会 治疗免疫抑制和免疫功能低下个体的 EBV+ B 细胞淋巴瘤。