Isolated Lymphoid Follicle in Aging

衰老中的孤立淋巴滤泡

• 批准号: 7123729
• 负责人: Rodney D Newberry
• 金额: $ 18.76万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7123729
• 关键词: B lymphocyte; aging; antibody specificity; chemokine; chemokine receptor; cytokine; electron microscopy; flow cytometry; gut associated lymphoid tissue; helper T lymphocyte; immunocytochemistry; immunoglobulin A; immunosenescence; inflammation; laboratory mouse; leukocyte activation /transformation; mucosal immunity; polymerase chain reaction; receptor expression; tumor necrosis factor beta

DESCRIPTION (provided by applicant): Immunosenescence is a state of dysregulated immune function contributing to the increased susceptibility of the elderly to infection, and potentially to an increased susceptibility to autoimmune diseases, chronic inflammatory diseases, and cancer. The impact of immunosenescence of the mucosal immune system is highlighted by epidemiological studies that document a marked increase in mortality due to gastrointestinal infections in the elderly and an increased incidence of inappropriate mucosal immune responses as manifested by the 'second peak' of inflammatory bowel disease in individuals in their seventh decade of life. The mechanisms resulting in immunosenescence of the mucosal immune system are largely unexplored. Isolated lymphoid follicles (ILFs) are inducible organized intestinal lymphoid structures. In young animals these structures act as sites for the induction of 'homeostatic' mucosal immune responses including the production of antigen specific IgA. The hypothesis of this study is that as a consequence of age-related changes in the inflammatory response to luminal stimuli, ILF formation is augmented and aberrant resulting in impaired protective immunity and a predisposition toward inappropriate mucosal immune responses. Consequently we will examine the aberrant formation and function of ILFs with aging in this proposal. In specific aim 1 we will use intestinal whole mounts stained with UEA-I lectin or anti-B220, immunohistochemistry, and flow cytometry to define the stage(s) of ILF formation that are augmented with aging. In specific aim 2 we will examine the production/expression of lymphotoxin, chemokines, and chemokine receptors which have been identified to contribute to/drive ILF formation using quantitative PCR and flow cytometry and correlate these findings with the previously identified roles for these factors driving the specific stages of ILF formation found to be augmented in specific aim 1. In specific aim 3 we will use immunhistochemistry, scanning and electron microscopy, flow cytometry, and in vitro cellular assays of cytokine production, and in vivo immunization to examine the function of ILFs in aging. The overall goal of this project is to understand how organ this specific dysfunction arises with aging, and to identify the factors/steps which are augmented with aging that act to drive this dysfunction. Future studies will attempt to manipulate specific steps in this process in a therapeutic manner.

描述（由申请人提供）：免疫衰老是一种免疫功能失调的状态，导致老年人对感染的易感性增加，并可能导致对自身免疫性疾病、慢性炎症性疾病和癌症的易感性增加。流行病学研究强调了粘膜免疫系统免疫衰老的影响，这些研究记录了老年人胃肠道感染导致的死亡率显着增加，以及不适当的粘膜免疫反应的发生率增加，这表现为炎症性肠病在70岁时出现“第二高峰”。导致粘膜免疫系统免疫衰老的机制在很大程度上尚未探索。孤立的淋巴滤泡（ILF）是可诱导的有组织的肠道淋巴结构。在幼年动物中，这些结构作为诱导“稳态”粘膜免疫应答的位点，包括抗原特异性伊加的产生。本研究的假设是，由于年龄相关的管腔刺激的炎症反应的变化，ILF形成增强和异常，导致保护性免疫受损和倾向于不适当的粘膜免疫反应。 因此，我们将研究ILF的异常形成和功能与衰老在这个建议。在具体目标1中，我们将使用用UEA-1凝集素或抗B220染色的肠全标本、免疫组织化学和流式细胞术来确定随着年龄增长而增加的ILF形成的阶段。在具体目标2中，我们将使用定量PCR和流式细胞术检查已被鉴定为有助于/驱动ILF形成的趋化因子、趋化因子和趋化因子受体的产生/表达，并将这些发现与先前鉴定的驱动ILF形成的特定阶段的这些因子的作用相关联，发现这些作用在具体目标1中得到增强。在具体目标3中，我们将使用免疫组织化学，扫描和电子显微镜，流式细胞术，细胞因子产生的体外细胞测定，以及体内免疫来检查ILF在衰老中的功能。该项目的总体目标是了解器官这种特定功能障碍如何随着衰老而出现，并确定随着衰老而增强的因素/步骤，这些因素/步骤会导致这种功能障碍。未来的研究将试图以治疗的方式操纵这一过程中的具体步骤。