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

摘要 衰老与免疫功能的剧烈变化有关，从而导致免疫力下降。 反应速度快，感染死亡率增加。潜在的机制仍然很差。 然而，我明白。目前，大多数信息来自于使用外周血液的研究，这 只含有大约2%的全身淋巴细胞(适应性免疫的关键效应者)。 这个隔区显示出与年龄相关的功能和组成的深刻变化。 记忆CD8+T淋巴细胞池，在很大程度上是由于日益不成比例的 血液中免疫细胞的积累，具有复制衰老的特点。这些被定义为像元 端粒较短，不能增殖和相关的表型变化。没有可靠的 关于人类胃肠道T淋巴细胞年龄相关变化的数据，这是 全身淋巴细胞的主要储存库和高抗原性暴露的解剖区域。 然而，我们对一群年轻人的初步研究发现，T 来自同一个人的肠道和血液之间的细胞表型。的首要目标是 拟议的研究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。根据数据显示 CD8+T淋巴细胞老化在很大程度上是由慢性病毒感染推动的，例如巨细胞病毒，我们将 评估慢性抗原刺激的影响也包括感染人类的人 免疫缺陷病毒。这种可治疗的慢性病毒感染使我们能够测试是否降低了 通过直接的病毒抑制，抗原性负荷延缓了衰老细胞与年龄相关的积累 通过减少慢性病毒感染对肠道的影响。目标1a将比较表型和 健康青年(20-35岁)和老年人(50-65岁)肠道和血液标本的功能参数 个人。目标1b将确定强烈的持续性抗原刺激对 血和血中CD8+T淋巴细胞亚群的正常年龄相关变化 相同年龄段的个体的胃肠粘膜，目标2将评估 减少CD8+T淋巴细胞聚集的治疗可延缓衰老CD8+T淋巴细胞聚集的GALT改变 病毒载量，从而达到慢性抗原刺激的水平。因此，拟议的研究将 首次全面分析与年龄相关的人类肠道变化，这是世界上最大的 体内的淋巴器官。就年龄而言，这一结果将具有重大的临床意义。 为不断增长的美国老年人口提供适当的治疗和疫苗开发。

ABSTRACT 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 is 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 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.