The mucosal immune system: effects of aging and chronic antigenic stimulation

描述（由申请人提供）：衰老与免疫功能的显著改变有关，导致免疫反应性降低和感染死亡率增加。然而，人们对其潜在机制仍知之甚少。目前，大多数信息来自使用外周血的研究，其中仅含有约2%的全身淋巴细胞（适应性免疫的关键效应器）。这表明记忆性CD8+ T淋巴细胞池的功能和组成发生了深刻的与年龄相关的变化，这在很大程度上是由于具有复制性衰老特征的血液免疫细胞越来越不成比例的积累。这些被定义为端粒短、不能增殖和相关表型改变的细胞。胃肠道是人体淋巴细胞的主要储存库，也是高抗原暴露的解剖区域，关于胃肠道中T淋巴细胞的年龄相关变化尚无可靠的数据。然而，我们对一组年轻人的初步研究表明，同一个体的肠道和血液中T细胞表型存在显著差异。拟议研究的总体目标是确定衰老对肠道相关淋巴组织（GALT）的影响，并分析慢性抗原刺激对这些变化的影响。基于提示CD8+ T淋巴细胞衰老主要由慢性病毒感染（如巨细胞病毒）驱动的数据，我们将通过包括感染人类免疫缺陷病毒的人来评估慢性抗原刺激的影响。这种可治疗的慢性病毒感染使我们能够测试是否通过直接抑制病毒来降低抗原负担，通过减少慢性病毒感染的影响来延缓肠道中衰老细胞的年龄相关积累。目的1a将比较健康年轻人（20-35岁）和老年人（50-65岁）的肠道和血液样本的表型和功能参数。Aim 1b将确定剧烈持续的抗原刺激对相同年龄组个体血液和胃肠道粘膜中CD8+ T淋巴细胞区室的规范年龄相关变化的附加影响，Aim 2将评估CD8+ T淋巴细胞积累的衰老GALT率的改变是否通过降低病毒载量的治疗而延缓，从而降低慢性抗原刺激的水平。因此，这项拟议的研究将首次全面分析人体肠道（人体最大的淋巴器官）中与年龄相关的变化。这一结果将对针对日益增长的美国老年人口的适龄治疗和疫苗开发具有重要的临床意义。公共卫生相关性：拟议的研究将首次全面分析人体肠道（人体最大的淋巴器官）中与年龄相关的免疫变化。研究结果将对适合年龄的治疗和为不断增加的老年人口开发疫苗具有重要的临床意义。此外，如果我们的研究表明肠道中免疫细胞的加速衰老是可逆的，这将刺激人们努力寻找新的治疗方法来增强老年人的免疫功能。

DESCRIPTION (provided by applicant): Aging is associated with dramatic alterations in immune function, resulting in reduced immunologic responsiveness and increased mortality from infections. The underlying mechanisms remain poorly understood, however. Currently, most information is derived from studies using peripheral blood, which contains approximately only 2% of total body lymphocytes (the key effectors of adaptive immunity). This compartment demonstrates a profound age-associated alteration in function and composition of the memory CD8+ T lymphocyte pool that is due, in large part, to the increasingly disproportionate accumulation of blood immune cells with features of replicative senescence. These are defined as cells with short telomeres, inability to proliferate and associated phenotypic changes. There are no reliable data on the age-related changes in T lymphocytes in the human gastrointestinal tract, which are the major reservoir of total body lymphocytes and an anatomical region of high antigenic exposure. However, our preliminary studies on a cohort of young individuals document significant differences in T cell phenotypes between the gut and blood from the same individual. The overarching goal of the proposed studies is to determine the effect of aging on gut-associated lymphoid tissue (GALT) and to analyze the impact of chronic antigenic stimulation on these changes. Based on data suggesting that CD8+ T lymphocyte aging is largely driven by chronic viral infections, such as cytomegalovirus, we will assess the impact of chronic antigenic stimulation by also including persons infected with the human immunodeficiency virus. This treatable chronic viral infection allows us to test whether lowering the antigenic burden, via direct viral suppression, retards the age-related accumulation of senescent cells in the gut by reducing the impact of the chronic viral infection. Aim 1a will compare phenotypic and functional parameters of gut and blood samples from healthy young (20-35 yrs) and older (50-65 yrs) individuals. Aim 1b will determine the additive impact of vigorous persistent antigenic stimulation on the normative age-related changes in the CD8+ T lymphocyte compartments within blood and gastrointestinal mucosa of individuals in the same age groups, and Aim 2 will evaluate whether the altered GALT rate of senescent of CD8+ T lymphocyte accumulation is retarded by treatment that reduces the viral load, and thus the level of chronic antigenic stimulation. The proposed research, will, therefore provide the first comprehensive analysis of age-associated changes in the human gut, the largest lymphoid organ in the body. The results will have significant clinical implications in terms of age-appropriate treatments and vaccine development for the ever increasing older U.S. population. PUBLIC HEALTH RELEVANCE: The proposed research will provide the first comprehensive analysis of age-associated immune changes in the human gut, the largest lymphoid organ in the body. The results will have significant clinical implications in terms of age-appropriate treatments and vaccine development for the ever-increasing older population. In addition, if our research shows that accelerated aging of the immune cells in the gut is reversible, this will stimulate efforts to identify novel therapeutic approaches for enhancing immune function in the elderly.