Innate immune control of the oncogenic Epstein Barr virus by natural killer (NK) cells

自然杀伤 (NK) 细胞对致癌 Epstein Barr 病毒的先天免疫控制

• 批准号: 200814771
• 负责人: Dr. Obinna Chijioke
• 金额: --
• 依托单位: Institut für Experimentelle Immunologie
• 依托单位国家: 德国
• 项目类别: Research Fellowships
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2012-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/200814771?language=en
• 关键词: Innate; immune; control; oncogenic; Epstein

The advent of highly immunodeficient mouse models that reconstitute human immune system components after transfer of hematopoietic progenitor cells opens the unique opportunity to address basic as well as translational questions to the biology of the human immune system in vivo. The guest lab headed by Christian Münz was able to establish engraftment of NSG mice with human CD34+ hematopoietic progenitor cells and consecutive development of functional human multi-lineage immune cells. Using this strategy Münz and colleagues could show that the reconstituted NSG mouse model reproduces key aspects of primary infection by the human oncogenic Epstein Barr virus (EBV) as well as EBV-associated tumors and T-cell mediated immune control thereof. Furthermore, we recently described the human natural killer (NK) cell compartment in reconstituted NSG mice and could demonstrate the functional competence of these innate lymphocytes. Since numerous studies have established the protective role of NK cells in the immune response against infections and cancer in mice, but conclusive evidence of this effect is lacking in humans, we now would like to address the role of human NK cells in vivo in the control of EBV infection and surveillance of EBV-induced tumors. For these studies we will characterize expansion and activation of human NK cell subsets during EBV infection in vivo, deplete or expand them during EBV infection and investigate the effects of these manipulations on viral titer and tumor development as well as characterize differences in T cell-mediated immune control upon these treatments. We think these approaches will allow us in a highly translational setting to contribute substantially to the understanding of the role of human NK cells in the control of EBV infection and tumor surveillance. The results obtained by these studies will likely broaden our insight into potential immunotherapeutic options of NK cells in the fight against viral infection and cancer.

在造血祖细胞转移后重建人免疫系统组分的高度免疫缺陷小鼠模型的出现为解决体内人免疫系统生物学的基本和转化问题提供了独特的机会。由Christian Münz领导的客座实验室能够在NSG小鼠中植入人CD 34+造血祖细胞，并连续开发功能性人多谱系免疫细胞。使用这种策略，Münz及其同事可以证明重建的NSG小鼠模型再现了人类致癌性Epstein巴尔病毒（EBV）原发感染的关键方面，以及EBV相关肿瘤和T细胞介导的免疫控制。此外，我们最近描述了人类自然杀伤（NK）细胞在重建的NSG小鼠，并可以证明这些先天淋巴细胞的功能能力。由于许多研究已经确定了NK细胞在小鼠抗感染和癌症的免疫应答中的保护作用，但在人类中缺乏这种作用的确凿证据，我们现在想解决人NK细胞在体内控制EBV感染和监视EBV诱导的肿瘤中的作用。对于这些研究，我们将表征在体内EBV感染期间人NK细胞亚群的扩增和活化，在EBV感染期间耗尽或扩增它们，并研究这些操作对病毒滴度和肿瘤发展的影响，以及表征这些治疗后T细胞介导的免疫控制的差异。我们认为，这些方法将使我们在一个高度翻译的环境中，大大有助于人类NK细胞在控制EBV感染和肿瘤监测中的作用的理解。这些研究获得的结果可能会拓宽我们对NK细胞在对抗病毒感染和癌症方面的潜在免疫选择的认识。