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）：免疫衰老是免疫功能失调的状态，导致老年人对感染的易感性增加，并有可能增加对自身免疫性疾病，慢性炎症性疾病和癌症的易感性。流行病学研究强调了粘膜免疫系统免疫衰老的影响，这些研究证明了老年人胃肠道感染引起的死亡率显着增加，并且粘膜免疫反应的发生率增加了，这表现为寿命十七世纪炎症性肠疾病的“第二峰”炎症性肠道疾病的“第二次峰值”。导致粘膜免疫系统免疫衰老的机制在很大程度上没有探索。分离的淋巴卵泡（ILF）是可诱导的有组织的肠道淋巴样结构。在年轻动物中，这些结构充当诱导“稳态”粘膜免疫反应的部位，包括产生抗原特异性IgA。这项研究的假设是，由于年龄相关的对腔刺激的炎症反应的变化，ILF形成的形成得到了增强，并异常，导致保护性免疫受损，并且对不适当的粘膜免疫反应的倾向。 因此，我们将在此提案中检查ILF随老化的异常形成和功能。在特定目标1中，我们将使用用UEA-I凝集素或抗B220，免疫组织化学和流式细胞仪染色的肠道整体坐骨来定义随着衰老增强的ILF形成期。在特定目的2中，我们将检查淋巴毒素，趋化因子和趋化因子受体的生产/表达，这些因子和趋化因子受体已被确定为使用定量PCR和流式细胞术有助于/驱动ILF形成/驱动ILF形成，并将这些发现与先前确定的对这些因素驱动特定级别的特定级别使用的特定阶段的因素相关的作用。显微镜，流式细胞术和细胞因子产生的体外细胞测定，以及体内免疫，以检查ILF在衰老中的功能。该项目的总体目标是了解这种特定功能障碍是如何随着衰老而引起的，并确定因衰老而增加的因素/步骤，这些因素会导致这种功能驱动这种功能障碍。未来的研究将尝试以治疗方式在此过程中操纵特定步骤。