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赤道非洲最普遍的伯基特淋巴瘤（EBL）的病因。 EBL的流行病学研究表明，儿童早期与恶性疟原虫疟疾和爱泼斯坦 - 巴尔病毒（EBV）感染有很强的联系。尽管尚不清楚疟疾-EBV相互作用如何增加EBL的风险，但已经提出疟疾中培养其抑制EBV特异性T细胞免疫。我们的中心假设是，全肺疟疾会损害EBV特异性效应子和中央记忆T细胞免疫的发展和维持。我们假设两种虽然不是相互排斥的，但机制是导致观察到的非洲儿童抑制EBV免疫力的原因：1）重复/慢性疟疾感染会导致高EBV病毒载荷，而CD45RA+重新表达效果的效果记忆CD8+ T细胞（TEMRA）的效果（Temra）的效果（Temra）更为效果（Temra），这又引起了CD45RA+重新表达的效果（Temra），而不是直接效应（Temra）。和/或2）重复/慢性疟疾感染减少了EBV特异性T细胞对稳态细胞因子的反应（即IL-15和IL-7）。该假设将通过检查患有疟疾病史和EBL儿童的健康肯尼亚儿童的EBV特异性免疫。具体目的将检验以下假设：目标1。累积暴露于疟疾和高EBV病毒载荷决定EBV-特异性CD8+ TEMRA的频率。 EBV特异性CD8+T细胞将使用HLA I类四聚体和T细胞子集进行定量，该子集定义为中央记忆TCM（CD45RA-CD62L+CCR7+）；效应器记忆，TEM（CD45RA-CD62L- CCR7-）; RA重新表达效应子记忆TEMRA（CD45RA+CD62L-CCR7-）。 EBV特异性的T细胞IFN-3产生，TCR V2使用和羧基氟烷酰亚胺基酯（CFSE）稀释的稀释度将在三组儿童之间进行比较。 AIM2。IL-15和/或IL-7 EBV特异性记忆T细胞的反应性受到慢性疟疾暴露儿童和EBL儿童的损害。 IL-15R1和IL-7R1表面表达，EBV特异性T细胞的CFSE响应于有或没有IL-15或IL7的同源抗原，以及三组儿童之间通过STAT5磷酸化测量的反应性。 AIM 3。累积暴露于疟疾和高EBV病毒载荷决定EBNA1-特异性记忆T细胞子集的频率。 EBNA1的重叠肽库将用于识别EBNA1-特异性IFN-3表达和增殖的记忆T细胞子集。在这三组儿童之间将比较增生的前体数量和产生EBNA1特异性T细胞的IFN-3的频率。鉴于大多数有关EBV T细胞免疫力的知识是基于对无症状成年人或感染性单核细胞增多症患者的检查，因此此处提出的研究将提供有关健康儿童以及患有EBL的EBV免疫进化的新信息。公共卫生相关性：伯基特淋巴瘤（BL）是一种普遍的小儿癌。了解BL病因将有助于预防这种侵略性的B细胞恶性肿瘤。这项研究的结果最终将改善成功的癌症免疫疗法的前景和与EBV相关的淋巴瘤（例如BL）的疫苗开发。