T Cell Immunity in Endemic Burkitt Lymphoma

地方性伯基特淋巴瘤中的 T 细胞免疫

• 批准号: 7632271
• 负责人: ANN M MOORMANN
• 金额: $ 37.01万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-05 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7632271
• 关键词: Accounting; Acute; Adolescent; Adult; Africa; African; African Burkitt' s lymphoma; Age; American; Antigens; Apoptosis; Area; B lymphoid malignancy; Burkitt Lymphoma; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Child; Childhood; Chronic; Cytomegalovirus; Data; Development; Diagnosis; Epidemiologic Studies; Epitopes; Epstein-Barr Virus Infections; Epstein-Barr Virus latency; Esters; Etiology; Europe; Evolution; Exposure to; Falciparum Malaria; Frequencies; Goals; Herpesviridae; Human Herpesvirus 4; IL7 gene; Immune; Immunity; Immunodominant Epitopes; Immunologic Monitoring; Immunosuppressive Agents; Infection; Infectious Mononucleosis; Interferons; Interleukin-10; Interleukin-15; Interleukin-4; Interleukin-7; Investigation; Kenya; Knowledge; Life; Lymphocyte Subset; Lymphoma; Lytic; Maintenance; Malaria; Malignant Childhood Neoplasm; Measures; Mediating; Memory; Outcome; Pathogenesis; Patients; Peptide Library; Peptides; Phosphorylation; Population; Populations at Risk; Prevention; Production; Proliferating; Prospective Studies; Recording of previous events; Research; Risk; Role; STAT5A gene; Specificity; Surface; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Time; Viral Load result; Viral Proteins; Viral load measurement; Virus Diseases; base; cancer immunotherapy; carboxyfluorescein; cytokine; cytotoxic; improved; interleukin-15 receptor; memory CD4 T lymphocyte; novel; persistent EBV infection; public health relevance; response; tumor; vaccine development

DESCRIPTION (provided by applicant): The long-term goal of this proposal is to understand the etiology of endemic Burkitt's lymphoma (eBL), the most prevalent pediatric cancer in equatorial Africa. Epidemiologic studies of eBL indicate a strong association with Plasmodium falciparum malaria and Epstein-Barr virus (EBV) infections early in childhood. Although it is not known how malaria-EBV interactions increase the risk of eBL, it has been suggested that malaria-mediates suppression of EBV-specific T cell immunity. Our central hypothesis is that holoendemic malaria impairs the development and maintenance of EBV-specific effector and central memory T cell immunity. We hypothesize that two, though not mutually exclusive, mechanisms are responsible for the observed suppression of EBV immunity in African children: 1) Repeat/chronic malaria infections result in high EBV viral load, that in turn induce `CD45RA+ re-expressing' effector memory CD8+ T cell (TEMRA) which display immediate IFN-3 expression but are more susceptible to apoptosis than effector memory T cells (TEM) and/or 2) Repeat/chronic malaria infections diminish EBV-specific T cell responsiveness to homeostatic cytokines (i.e. IL-15 and IL-7). This hypothesis will be tested by examination of EBV-specific immunity in healthy Kenyan children with divergent malaria exposure histories and of eBL children. The specific aims will test the following hypotheses: Aim 1. Cumulative exposure to malaria and high EBV viral load determine the frequencies of EBV- specific CD8+ TEMRA. EBV-specific CD8+ T cells will be quantified using HLA Class I tetramers and T cell subsets defined as central memory, TCM (CD45RA-CD62L+CCR7+); effector memory, TEM (CD45RA-CD62L- CCR7-); and RA re-expressing effector memory, TEMRA (CD45RA+CD62L-CCR7-). EBV-specific T cell IFN-3 production, TCR V2 usage and proliferation by carboxyfluorescein succinimidyl ester (CFSE) dilution will be compared between the three groups of children. Aim 2. IL-15 and/or IL-7 responsiveness of EBV-specific memory T cells is impaired in children with chronic malaria exposure and in children with eBL. IL-15R1 and IL-7R1 surface expression, CFSE proliferation of EBV-specific T cells in response to cognate antigen with and without IL-15 or IL7, and responsiveness measured by STAT5 phosphorylation will be compared between the three groups of children. Aim 3. Cumulative exposure to malaria and high EBV viral load determine the frequencies of EBNA1- specific memory T cell subsets. Overlapping peptide libraries of EBNA1 will be used to identify EBNA1- specific IFN-3 expressing and proliferating memory T cell subsets. The precursor numbers of proliferating and the frequency of IFN-3 producing EBNA1-specific T cells will be compared between the three groups of children. Given that most knowledge regarding EBV T cell immunity is based on examination of asymptomatic adults or those who have had infectious mononucleosis, studies proposed here will provide novel information with respect to the evolution of EBV immunity in healthy children as well as those with eBL. PUBLIC HEALTH RELEVANCE: Burkitt lymphoma (BL) is a prevalent pediatric cancer. Understanding BL etiology will aid in the prevention of this aggressive B cell malignancy. Results from this research will ultimately improve the prospects for successful cancer immunotherapies and vaccine development for EBV-associated lymphomas such as BL.

描述（由申请人提供）：该提案的长期目标是了解地方性伯基特淋巴瘤（eBL）的病因，这是赤道非洲最常见的儿科癌症。 eBL 的流行病学研究表明，与儿童早期的恶性疟原虫疟疾和 Epstein-Barr 病毒 (EBV) 感染密切相关。尽管尚不清楚疟疾-EBV 相互作用如何增加 eBL 风险，但有人认为疟疾介导了 EBV 特异性 T 细胞免疫的抑制。我们的中心假设是，全地方性疟疾会损害 EBV 特异性效应器和中枢记忆 T 细胞免疫的发育和维持。我们假设有两种机制（尽管并不相互排斥）导致非洲儿童中观察到的 EBV 免疫抑制：1) 重复/慢性疟疾感染导致高 EBV 病毒载量，进而诱导“CD45RA+ 重新表达”效应记忆CD8+ T 细胞 (TEMRA) 表现出即时 IFN-3 表达，但比效应记忆 T 细胞 (TEM) 更容易凋亡和/或 2) 重复/慢性疟疾感染会减少 EBV 特异性 T细胞对稳态细胞因子（即 IL-15 和 IL-7）的反应。这一假设将通过检查具有不同疟疾暴露史的健康肯尼亚儿童和 eBL 儿童的 EBV 特异性免疫力来检验。具体目标将检验以下假设： 目标 1. 累积接触疟疾和高 EBV 病毒载量决定 EBV 特异性 CD8+ TEMRA 的频率。将使用 HLA I 类四聚体和定义为中央记忆、TCM (CD45RA-CD62L+CCR7+) 的 T 细胞亚群对 EBV 特异性 CD8+ T 细胞进行定量；效应存储器，TEM（CD45RA-CD62L-CCR7-）；和 RA 重新表达效应记忆，TEMRA (CD45RA+CD62L-CCR7-)。将比较三组儿童的 EBV 特异性 T 细胞 IFN-3 产生、TCR V2 使用情况以及羧基荧光素琥珀酰亚胺酯 (CFSE) 稀释液的增殖情况。目标 2. 慢性疟疾暴露儿童和 eBL 儿童中 EBV 特异性记忆 T 细胞的 IL-15 和/或 IL-7 反应性受损。将比较三组儿童之间的 IL-15R1 和 IL-7R1 表面表达、EBV 特异性 T 细胞响应同源抗原（有或没有 IL-15 或 IL7）的 CFSE 增殖，以及通过 STAT5 磷酸化测量的反应性。目标 3. 疟疾的累积暴露和高 EBV 病毒载量决定了 EBNA1 特异性记忆 T 细胞亚群的频率。 EBNA1 的重叠肽文库将用于鉴定 EBNA1 特异性 IFN-3 表达和增殖记忆 T 细胞亚群。将比较三组儿童的增殖前体数量和产生 IFN-3 的 EBNA1 特异性 T 细胞的频率。鉴于大多数关于 EBV T 细胞免疫的知识都是基于对无症状成人或患有传染性单核细胞增多症的人的检查，本文提出的研究将提供有关健康儿童以及 eBL 儿童 EBV 免疫进化的新信息。公共卫生相关性：伯基特淋巴瘤 (BL) 是一种常见的儿科癌症。了解 BL 病因将有助于预防这种侵袭性 B 细胞恶性肿瘤。这项研究的结果将最终改善 BL 等 EB 病毒相关淋巴瘤的成功癌症免疫疗法和疫苗开发的前景。