Characterization of Immune Alterations Associated with the Aging Process

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。然而，尽管有许多关于免疫功能随年龄变化的发现，但人们对这种变化发生的原因以及免疫细胞亚群及其活动的变化如何影响老年人和/或各种疾病状态下的免疫功能知之甚少。这项正在进行的研究利用了来自不同年龄的正常健康志愿者的外周血细胞或老年啮齿动物和灵长类动物的细胞，以深入了解人类免疫功能与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。我们最近的一项发现表明，老年淋巴细胞比年轻的T细胞产生更多的腺苷，这与腺苷2A受体介导的免疫抑制相互作用。目前正在探索腺苷在免疫衰老中的确切作用。此外，我们发现，与年轻动物相比，各种免疫治疗策略对中老年小鼠具有相当大的毒性，并且这种发病率的增加与巨噬细胞、TNF和肥胖有关。TNF-R活性拮抗剂阻止了这些毒性，并在老年动物中提供了更大的抗肿瘤作用。这些研究表明，对于老年动物甚至人类的免疫治疗，联合疗法可能是必要的。总的来说，由于免疫亚群（如T细胞、巨噬细胞、NK细胞）的数量和百分比随着年龄和各种疾病状态的变化而发生显著变化，我们相信，对这些亚群、它们的细胞因子表达谱及其在疾病进展中的作用进行更详细的分析，不仅可以获得与衰老和疾病相关的免疫缺陷的有价值信息，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. However, despite the many findings on alterations in immune function with age, very little is known about the why such changes occur and how alterations in immune cell subsets and their activities influence immune function in the elderly and/or during various disease states. The ongoing work utilizes either peripheral white blood cells obtained from normal healthy volunteers of different ages or cells from aged rodents and primates 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. One of our recent findings demonstrated that aged lymphocytes produce more adenosine than younger T cells, which interacts with the adenosine 2A receptor mediating immunosuppression. The precise role of adenosine in immunosenescence is currently being explored. In addition, we have found that various immunotherapeutic strategies are quite toxic for middle aged and old mice compared to younger animals and that this increase in morbidity is associated with macrophages, TNF and adiposity. Antagonists to TNF-R activity prevented these toxicities and provided a greater effect on anti-tumor effects in older animals. These studies suggest that combinational therapies may be necessary for immunotherapeutic treatments in older animals and possibly humans. Overall, as immune subsets (e.g., T cells, macrophages, NK cells) have been shown to be dramatically change in numbers and percentages with age and during various disease states, we believe that more detailed analysis of these subsets, their cytokine expression profile and their role in disease progression 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.