AGE-ASSOCIATED ALTERATIONS IN HUMAN NK CELL SYSTEM

人类 NK 细胞系统中与年龄相关的变化

• 批准号: 3116454
• 负责人: RAJABATHER KRISHNARAJ
• 金额: $ 8.33万
• 依托单位: EVANSTON HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1985
• 资助国家: 美国
• 起止时间: 1985-08-01 至 1988-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3116454
• 关键词: adenosine triphosphate; aging; antiantibody; cell biology; cell population study; cytogenetics; cytotoxicity; human age group; human middle age (35-64); human old age (65+); immunofluorescence technique; immunopharmacology; interferons; lymphocyte; mathematical model; monoclonal antibody; neoplasm /cancer immunology; radiotracer; single cell analysis; spectrometry; surface antigens

Alterations in the Natural Killer (NK) cell system in healthy humans will be investigated in a comprehensive cross-sectional study with special reference to aging. In view of the elevated incidence of neoplasia in the elderly, it is important to learn about the NK cell biology in healthy aged humans. Studies by others on this subject have been very limited, performed on impure cell preparations employing a single, conventional semi-quantitative assay and yielded conflicting results. The multi-technique approach used in our preliminary studies have revealed that the healthy elderly (greater than 80 yr) represent a homogeneous group, expressing an average peripheral blood NK cell activity higher than that of younger adults (20-40 yr). We propose to investigate the alterations in the NK cell frequency and expression by performing cytolytic funtional assays, kinetic analysis of tumor target lysis, surface phenotype (N-901, Leu-7 and Leu-11a) determination, differential sensitivity to ATP (a negative modulator of NK activity), and interferon as well as and an assessment of the critical steps in NK cytolysis (target binding, frequency of active NK cells and recycling capacity) by using a single-cell assay on semi-solid matrix. Highly enriched large granular lymphocytes from 300 healthy volunteers (20-100 yrs) will be utilized. Correlations will be sought between the NK cell surface marker expression and many of the cytolytic steps that may distinguish the individuals in the intra- and inter-age groups. Influence of age on the NK cell recycling capacity and its interacting ability with tumor targets will be examined. We will also examine the cause(s) for an elevated maximal cytotoxic potential (Vmax) exhibited by the elderly (greater than 80 yr). We will determine if the NK activity per cell or NK cell frequency goes up with age. Furthermore, based on a proposition that the higher level of NK activity in the greater than 80 yr old humans may be attributable to a deletion of a population of younger individuals with lower NK activity, a late-life (greater than 70 yr) longitudinal study will be initiated. Accomplishment of these objectives might reveal if the critical cytolytic steps that distinguish the low and high NK activity of young adults are the same that separate the younger from the elderly NK cell features, helping to elucidate age-associated modulations. It is also hoped that the results might form a basis for future pharmacological interventions.

健康人自然杀伤(NK)细胞系统的改变将 在全面的横断面研究中被调查，特别是 指的是衰老。鉴于中国的肿瘤发病率较高 老年人，了解健康老年人的NK细胞生物学很重要 人类。其他人对这一主题的研究非常有限， 在不纯细胞制剂上使用单一的、常规的 半定量测定，并产生了相互矛盾的结果。这个 我们在初步研究中采用的多种技术方法表明， 健康老年人(>80岁)代表一个同质性的群体， 表达的平均外周血NK细胞活性高于 年轻人(20-40岁)。我们建议调查一下 细胞溶解功能对NK细胞频率和表达的影响 检测，肿瘤靶点裂解动力学分析，表面表型(N-901， Leu-7和Leu-11a)测定，对ATP(A)的微分敏感性 NK活性的负调节因子)、干扰素以及 评估NK细胞溶解的关键步骤(靶标结合、频率 活性NK细胞和循环能力)通过使用单细胞检测 半固态基质。高度浓缩的300份大颗粒淋巴细胞 健康志愿者(20-100岁)将被使用。相关性将是 寻找NK细胞表面标志物的表达与许多 细胞溶解步骤可以区分细胞内和细胞内的个体 各年龄段的人。年龄对自然杀伤细胞循环能力的影响 它与肿瘤靶点的相互作用能力将被检测。我们还将 检查最大细胞毒潜力升高的原因(S) 由老年人(80岁以上)展出。我们将确定朝鲜是否会 每个细胞的活性或NK细胞频率随着年龄的增长而增加。此外， 基于一种命题，即NK活性水平越高， 超过80岁的人类可能归因于 NK活性较低的年轻个体，晚年(大于70岁) 年)将启动纵向研究。实现这些目标 目标可能会揭示区分不同的关键细胞溶解步骤 青壮年NK活性低和高的差异是相同的。 来自老年人的年轻NK细胞的特点，有助于阐明 年龄相关的调制。人们还希望，选举结果可能会形成一个 为未来的药理学干预奠定了基础。