Characterization of Immune Alterations Associated with t

人类和动物免疫功能与年龄相关的变化不仅对老年人的总体健康很重要，而且对免疫系统本身的总体特征也很重要。研究表明，老年人更容易受到病毒和细菌感染，也更容易患癌症。对于在老年人中观察到的免疫反应减弱，有许多假设，包括胸腺退化、主动免疫抑制、免疫细胞复制衰老、细胞信号缺陷和细胞因子表达谱的改变。一系列临床研究表明，与年轻人相比，老年人对疫苗的细胞和体液免疫反应较差，即使有标准佐剂存在。目前，许多实验室正把研究重点放在开发更有效的兴奋剂上，以配合已知的疫苗在老年人中进行试验。然而，在衰老过程中，先天和获得性免疫功能的改变描述不佳，限制了治疗干预。目前的项目利用从不同年龄的正常健康志愿者中获得的外周血细胞来深入了解人类免疫功能年龄相关变化的生物学、生化和分子机制。与从年轻个体获得的免疫细胞相比，老年白细胞也显示出独特的蛋白质磷酸化、细胞因子合成和基因表达模式，对细胞迁移和运输以及细胞周期进展的影响。此外，目前正在研究从不同年龄的人类和灵长类动物中分离的CD28-和CD57+ T细胞的原代和克隆培养。由于这些免疫亚群在各种疾病状态（包括关节炎、艾滋病和衰老）的循环中急剧增加，我们相信，对这些亚群进行更详细的分子和生化分析不仅会产生与衰老和疾病相关的免疫缺陷的有价值的信息，还可能导致可能的免疫治疗干预，以增强免疫反应。

Age-associated changes in immune function in humans and animals are quite important with regard not only to the general health of aged persons but also to the general features of the immune system itself. Elderly subjects have been shown to be more susceptible to viral and bacterial infections and are believed to be more susceptible to cancer. There have been a number of hypotheses for the diminished immune responses observed in elderly subjects including involution of the thymus, active immunosuppression, replication senescence of immune cells, cellular signaling defects, and alterations in cytokine expression profiles. A series of clinical studies has revealed that elderly subjects, in contrast to their younger counterparts, exhibit poor cellular and humoral immune responses to vaccines even in the presence of standard adjuvants. Currently, many laboratories are focusing their research efforts into developing more effective stimulants for use with known vaccines to be tested with elderly populations. However, the poor description of alterations in innate and acquired immune function during the aging process has limited therapeutic intervention. The current project utilizes peripheral white blood cells obtained from normal healthy volunteers of different ages to gain insight into the biological, biochemical, and molecular mechanisms underlying age-associated changes in human immune function. In comparison with immune cells obtained from younger individuals, aged leukocytes also display distinctive patterns of protein phosphorylation, cytokine synthesis and gene expression, effects on cell migration and trafficking, and cell-cycle progression. In addition, studies are currently underway examining primary and clonal cultures of CD28- and CD57+ T cells cultures isolated from humans and primates of different ages. As these immune subpopulations are dramatically increased in the circulation during various disease states (including arthritis, AIDS, and aging), we believe that more detailed molecular and biochemical analysis of these subsets will not only yield valuable information about the immune deficits associated with aging and disease but may also lead to possible immunotherapeutic interventions to boost immune responses. More specific efforts are also underway examining the differences in the make-up of lipid rafts within the cell membranes of young and aged lymphocytes. Given the large number of alterations in lipid peroxidation and metabolism with age, changes in the types, saturation and levels of various membrane sphingolipids, fatty acids and cholesterol may result in specific changes in membrane fluidity, protein association and aggregation, cellular activation and function. In addition, through HPLC separation, 2-D gel electrophoresis and mass spectroscopy, additional studies are underway creating a proteomic expression profile of the various proteins within the lipid rafts of young and aged lymphocytes at various stages of activation. We believe that a greater understanding of the various signaling and cell surface proteins associated with lipid rafts may provide great insight into age-related alterations in cell signaling and activation. Due to limits on human leukocyte availability from aged donors, we have focused some of our efforts on animal models and have demonstrated significant age-related phenotypic and molecular changes in both murine and primate T-cells and accessory cells.