UNDERSTANDING THE ROLE OF EPSTEIN BARR VIRUS IN T CELL AND NATURAL KILLER CELL LYMPHOPROLIFERATIONS AND MALIGNANCIES

了解 Epstein Barr 病毒在 T 细胞和自然杀伤细胞淋巴细胞增殖和恶性肿瘤中的作用

• 批准号: MR/N023781/1
• 负责人: Claire Shannon-Lowe
• 金额: $ 41.87万
• 依托单位: University of Birmingham
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN023781%2F1
• 关键词: UNDERSTANDING; ROLE; EPSTEIN; BARR; VIRUS

Epstein Barr virus (EBV) is a common herpesvirus that infects the majority of the human population for the lifetime of each individual. The vast majority of individuals are unaware that they have been infected because the virus is kept under tight control by their immune system. Although EBV is most well known for causing glandular fever, it is also associated with cancers in a small number of individuals. These cancers usually occur in the cells infected as part of the natural life cycle of the virus, B lymphocytes and epithelial cells. However, on rare occasions EBV can also infect cells that are not involved in the lifecycle of the virus, T lymphocytes and Natural killer (NK) cells. Infection of these cell types always results in serious, life-threatening diseases including cancers. These diseases are extremely difficult to treat and have a very poor clinical outcome, usually measured in survival from weeks to months. There is an urgent need to better understand the pathology of these EBV-associated T/NK cell diseases in order to develop new effective, personalized therapies.Progress into understanding these diseases has been extremely slow, due to the rarity of the diseases and our inability to infect T/NK cells in the lab. However, we have addressed both these issues. We currently have a bank of blood samples from UK patients with EBV-associated T/NK cell diseases ready for analysis. Furthermore we have optimized the culture conditions and have generated matching EBV-positive T/NK cell lines from the patients' samples. Finally, and perhaps most importantly, we have managed to reproducibly infect T cells in our laboratory, which for the first time will allow us to examine how EBV triggers these T/NK cell diseases and induces their transformation into malignancy. We have four key objectives. (1) Using patient blood, we have identified white blood cells and chemical signals (cytokines) from the microenvironment which are required to help the patients' EBV-infected T/NK cells to grow in culture. We plan to replicate these conditions in the lab to help the newly-infected T/NK cells grow and determine how EBV, the surrounding cells and cytokines contribute to the growth of newly-infected T/NK cells. (2) Once the growth conditions are optimized, we will examine how specific EBV gene products able to stimulate the chronic inflammation observed in the EBV-associated T/NK cell diseases. (3) By replicating the EBV infection and chronic inflammation in our cell cultures, we will examine how EBV and chronic inflammation drive the infected cells to grow indefinitely and dysregulate the anti-EBV immunity. (4) We have established a new analysis tool, which labels the EBV-infected cells with markers for EBV and markers for the cell type. We can expand the range of markers to identify potential new drug targets on the EBV-infected cell to include therapeutic antibodies such as anti-CCR4 (mogamulizumab) currently in phase 2 clinical trial for peripheral T cell lymphoma. Furthermore, we can culture the matching ex-vivo EBV-infected T/NK cells, as above, in the presence of the drug to determine sensitivity to the drug. This is the first study of its kind to analyse the contribution of EBV to the EBV-associated T/NK cell diseases by combining ex-vivo patient samples and primary infected T/NK cells. We anticipate that by understanding how EBV causes the diseases, either directly or in combination with other cells and cytokines of the surrounding microenvironment, and by monitoring disease progression both in vitro and in vivo, we will develop a better understanding of alternative novel therapeutic options. Finally, the assays we have established to examine the potential new treatments will have wider benefit to the EBV-associated T/NK cell disease patient groups if the study were taken to trial, based on the findings of this study. The results will identify potential drugs for personalized treatment options.

爱泼斯坦巴尔病毒（EBV）是一种常见的疱疹病毒，在每个人的一生中感染大多数人类。绝大多数人不知道他们已经被感染，因为病毒被他们的免疫系统严密控制。虽然EB病毒是最众所周知的引起腺热，它也与癌症在少数人。这些癌症通常发生在作为病毒自然生命周期的一部分被感染的细胞、B淋巴细胞和上皮细胞中。然而，在极少数情况下，EBV也可以感染不参与病毒生命周期的细胞，T淋巴细胞和自然杀伤（NK）细胞。这些细胞类型的感染总是导致严重的，危及生命的疾病，包括癌症。这些疾病极难治疗，临床结果非常差，通常以存活数周至数月来衡量。目前迫切需要更好地了解这些EBV相关T/NK细胞疾病的病理学，以便开发新的有效的个性化治疗方法。由于这些疾病的罕见性以及我们无法在实验室中感染T/NK细胞，因此了解这些疾病的进展非常缓慢。然而，我们已经解决了这两个问题。我们目前有一个英国EBV相关T/NK细胞疾病患者的血液样本库，可供分析。此外，我们优化了培养条件，并从患者的样品中产生了匹配的EBV阳性T/NK细胞系。最后，也许也是最重要的一点，我们已经成功地在实验室中可重复地感染了T细胞，这将首次使我们能够研究EBV如何触发这些T/NK细胞疾病并诱导它们转化为恶性肿瘤。我们有四个主要目标。(1)使用患者血液，我们已经从微环境中鉴定出白色血细胞和化学信号（细胞因子），其是帮助患者的EBV感染的T/NK细胞在培养物中生长所需的。我们计划在实验室中复制这些条件，以帮助新感染的T/NK细胞生长，并确定EBV、周围细胞和细胞因子如何促进新感染的T/NK细胞的生长。(2)一旦生长条件优化，我们将研究特定的EB病毒基因产物如何刺激EB病毒相关T/NK细胞疾病中观察到的慢性炎症。(3)通过在我们的细胞培养物中复制EBV感染和慢性炎症，我们将研究EBV和慢性炎症如何驱动受感染的细胞无限期生长并使抗EBV免疫失调。(4)我们建立了一种新的分析工具，它用EB病毒标记物和细胞类型标记物标记EB病毒感染的细胞。我们可以扩大标记物的范围，以确定EBV感染细胞上潜在的新药物靶点，包括治疗性抗体，如目前在外周T细胞淋巴瘤2期临床试验中的抗CCR 4（mogamulizumab）。此外，我们可以如上所述在药物存在下培养匹配的离体EBV感染的T/NK细胞，以确定对药物的敏感性。这是第一项通过结合离体患者样本和原发性感染T/NK细胞来分析EBV对EBV相关T/NK细胞疾病的贡献的研究。我们预计，通过了解EBV如何直接或与周围微环境的其他细胞和细胞因子结合引起疾病，并通过监测体外和体内疾病进展，我们将更好地了解替代性新治疗方案。最后，我们已经建立了检测潜在新治疗方法的试验，如果根据本研究的结果进行试验，将对EBV相关T/NK细胞疾病患者群体产生更广泛的益处。研究结果将为个性化治疗选择确定潜在的药物。

项目成果

SARS-CoV-2 Causes a Different Cytokine Response Compared to Other Cytokine Storm-Causing Respiratory Viruses in Severely Ill Patients.

• DOI: 10.3389/fimmu.2021.629193
• 发表时间: 2021
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Olbei M;Hautefort I;Modos D;Treveil A;Poletti M;Gul L;Shannon-Lowe CD;Korcsmaros T
• 通讯作者: Korcsmaros T

From pathobiology to targeted treatment in Epstein Barr virus related T cell and Natural Killer cell lymphoproliferative diseases

EB病毒相关T细胞和自然杀伤细胞淋巴增殖性疾病从病理学到靶向治疗

• DOI: 10.21037/aol-21-33
• 发表时间: 2021
• 期刊: Annals of Lymphoma
• 作者: Glover A

Pumilio directs deadenylation-associated translational repression of the cyclin-dependent kinase 1 activator RGC-32.

• DOI: 10.1093/nar/gky038
• 发表时间: 2018-04-20
• 期刊: Nucleic acids research
• 影响因子: 14.9
• 作者: Brocard M;Khasnis S;Wood CD;Shannon-Lowe C;West MJ
• 通讯作者: West MJ

Characterizing EBV-associated lymphoproliferative diseases and the role of myeloid-derived suppressor cells

• DOI: 10.1182/blood.2020005611
• 发表时间: 2021-01-14
• 期刊: BLOOD
• 影响因子: 20.3
• 作者: Collins, Paul J.;Fox, Christopher P.;Shannon-Lowe, Claire
• 通讯作者: Shannon-Lowe, Claire

Early T Cell Recognition of B Cells following Epstein-Barr Virus Infection: Identifying Potential Targets for Prophylactic Vaccination.

• DOI: 10.1371/journal.ppat.1005549
• 发表时间: 2016-04
• 期刊: PLoS pathogens
• 影响因子: 6.7
• 作者: Brooks JM;Long HM;Tierney RJ;Shannon-Lowe C;Leese AM;Fitzpatrick M;Taylor GS;Rickinson AB
• 通讯作者: Rickinson AB