A prospective analysis of peripheral blood cytokines and non-Hodgkin lymphoma

外周血细胞因子与非霍奇金淋巴瘤的前瞻性分析

基本信息

批准号：
8508681
负责人：
BRENDA M BIRMANN
金额：
$ 56.02万
依托单位：
BRIGHAM AND WOMEN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-09-01 至 2016-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8508681
关键词：
Address Adult Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Basic Science Biological Assay Biological Markers Blood specimen C-reactive protein CXCL13 gene Cancer Etiology Cell Lineage Cessation of life Chronic Clinical Sciences Cohort Studies DNA Data Analyses Diagnosis Diagnostic Early Diagnosis Elderly Epidemiologist Epstein-Barr Virus Infections Etiology Future Health Professional Hematologic Neoplasms High-Risk Cancer Histologic Hormones Human Human Herpesvirus 4 IL2RA gene IgE Immune Immune response Immunocompetent Immunologic Markers Immunologist Immunosuppression Inflammation Inflammatory Inflammatory Response Interleukin 2 Receptor Interleukin-6 Knowledge Logistic Regressions Lymphocyte Activation Malignant - descriptor Malignant Neoplasms Measures Mediating Minority Modification Molecular Non-Hodgkin&apos s Lymphoma Nurses&apos Health Study Pathologic Pathology Patients Pattern Persons Plasma Population Prevalence Prevention strategy Process Production Prospective Studies Public Health Publishing Qualifying Questionnaires Reporting Resources Risk Risk Factors Role Sampling Specimen T-Cell Activation T-Lymphocyte TNFR-Fc fusion protein TNFRSF8 gene Technology Testing Tissue Microarray Tissues Tumor Necrosis Factor-alpha United States World Health Organization base biobank cancer diagnosis cohort cytokine digital imaging experience follow-up innovation insight large cell Diffuse non-Hodgkin&apos s lymphoma lymphoid neoplasm multidisciplinary novel peripheral blood population based prospective response tumor

项目摘要

DESCRIPTION (provided by applicant): Non-Hodgkin lymphoma (NHL) comprises a heterogeneous group of >30 lymphoid neoplasms, >85% of which are of B cell lineage. NHL presents a considerable public health burden with >80,500 new diagnoses and 24,600 deaths expected in 2010. The etiology of NHL is poorly understood, but it is known that overt immune compromise is a strong risk factor. Immune dysregulation may also be important in the etiology of NHL in persons with no overt immune deficiency. The Epstein-Barr virus (EBV) is detected in a sizeable minority of NHL in immune competent persons, but neither the true prevalence nor risk factors for EBV+ NHL are known. Th17, Th1, and Th2 cytokines mediate human immune responses and may be associated with NHL risk by virtue of their roles in B and T lymphocyte activation and inflammation. The Th17 response leads to the induction of several B cell stimulatory cytokines; this axis is also implicated in autoimmune disease, and persons with autoimmune conditions have an increased risk of NHL. It is plausible that Th17 dysregulation, and/or dysregulation of Th1 or Th2 or inflammatory responses, is associated with NHL risk in apparently immune competent adults. Cytokines also mediate host control of EBV and thus may also predict risk of EBV+ NHL. To examine these hypotheses, we will conduct prospective studies nested within the Nurses' Health Study and Health Professionals Follow-up Study cohorts. In a projected pooled sample of 670 cases and 1340 matched controls, we will measure a panel of immune markers in pre-diagnostic plasma samples. We will collect tissue specimens from NHL cases for pathologic studies to determine WHO-defined histologic subtype, diffuse large B-cell lymphoma (DLBCL) molecular subtype, and EBV status. We will use conditional logistic regression to assess the association of plasma immune markers indicative of altered Th17, Th1, Th2 and/or inflammatory responses with NHL. We will evaluate confounding by other NHL risk factors and conduct secondary analyses to examine effect modification and explore the correlation of plasma immune markers with those other factors. With these studies we will be the first to examine the etiologic role of the Th17 response in NHL, to report population-based prevalences of EBV+ NHL by subtype and of DLBCL subtypes, and to prospectively evaluate risk factors for EBV+ NHL. The multidisciplinary study team features epidemiologists (Drs. Birmann, Laden, and Giovannucci), a senior biostatistician (Dr. Rosner), and immunologists (Drs. Martmnez-Maza and Breen) and hematopathologists (Drs. Aster and Rodig) with substantial relevant experience-i.e, in the use of plasma immune markers in etiologic studies, prospective data analysis, and the pathologic determination of NHL histologic type and tumor EBV status. With this highly qualified team, the extraordinary resources of the cohorts, and the proposed studies, we are uniquely situated to contribute novel insights on the role of immune dysregulation in the etiology of NHL and EBV+ NHL in immunocompetent adults.

描述（由申请人提供）：非霍奇金淋巴瘤 (NHL) 包含超过 30 种淋巴肿瘤的异质组，其中超过 85% 属于 B 细胞谱系。 NHL 给公共健康带来了相当大的负担，预计 2010 年将有超过 80,500 例新诊断病例和 24,600 例死亡病例。NHL 的病因尚不清楚，但众所周知，明显的免疫损害是一个强大的危险因素。对于没有明显免疫缺陷的人来说，免疫失调在 NHL 的病因学中也可能很重要。 EB 病毒 (EBV) 在免疫能力正常的 NHL 患者中检测到，但 EBV+ NHL 的真实患病率和危险因素尚不清楚。 Th17、Th1 和 Th2 细胞因子介导人类免疫反应，并且由于其在 B 和 T 淋巴细胞活化和炎症中的作用，可能与 NHL 风险相关。 Th17 反应会诱导多种 B 细胞刺激性细胞因子的产生；该轴还与自身免疫性疾病有关，患有自身免疫性疾病的人患 NHL 的风险增加。 Th17 失调和/或 Th1 或 Th2 失调或炎症反应可能与表面上具有免疫能力的成年人的 NHL 风险相关。细胞因子还介导宿主对 EBV 的控制，因此也可以预测 EBV+ NHL 的风险。为了检验这些假设，我们将在护士健康研究和健康专业人员随访研究队列中进行前瞻性研究。在由 670 例病例和 1340 名匹配对照组成的预计合并样本中，我们将测量诊断前血浆样本中的一组免疫标记物。我们将从 NHL 病例中收集组织标本进行病理研究，以确定 WHO 定义的组织学亚型、弥漫性大 B 细胞淋巴瘤 (DLBCL) 分子亚型和 EBV 状态。我们将使用条件逻辑回归来评估指示 Th17、Th1、Th2 改变和/或炎症反应与 NHL 的血浆免疫标记物的关联。我们将评估其他 NHL 危险因素的混杂因素，并进行二次分析以检查效果修正并探索血浆免疫标志物与其他因素的相关性。通过这些研究，我们将首先检查 Th17 反应在 NHL 中的病因作用，报告基于人群的 EBV+ NHL 按亚型和 DLBCL 亚型的患病率，并前瞻性评估 EBV+ NHL 的危险因素。多学科研究团队由具有丰富相关经验的流行病学家（Birmann、Laden 和 Giovannucci 博士）、高级生物统计学家（Rosner 博士）、免疫学家（Martmnez-Maza 和 Breen 博士）以及血液病理学家（Aster 和 Rodig 博士）组成。 -即，在病因学研究、前瞻性数据分析以及 NHL 组织学类型和病理学确定中使用血浆免疫标记物肿瘤 EBV 状态。凭借这个高素质的团队、队列的非凡资源以及拟议的研究，我们具有独特的优势，能够就免疫失调在免疫功能正常的成人 NHL 和 EBV+ NHL 病因学中的作用提供新的见解。