AGE-ASSOCIATED ALTERATIONS IN HUMAN NK CELL SYSTEM

鉴于老年人肿瘤发病率较高， 自然杀伤（NK）细胞系统将在健康人体中进行研究 特别提到老化。我们建议批判性地研究原因 大多数健康人体内的 NK 系统都非常活跃（正如我们所发现的） 尽管 T&B 细胞下降，但老年人（80 岁以上） 反应性。如果 IL-2 缺乏是导致 T 细胞缺陷的原因， NK细胞如何逃脱？我们的前提是最终的改变 细胞因素（NK效应子和祖细胞频率）和/或体液因素 因子（淋巴因子）可能是造成这些变化的原因。至 为了实现这个目标，我们将枚举 NK 子集（CD2 的共表达， CD8、CD11a、CD11b 和 CD18（带有主要 NK 标记 Leu-19、CD16 和 Leu-7）和 确定它们对 NK 总溶细胞潜力的贡献 细胞。血浆水平和淋巴细胞分泌IL-2和的能力 将测量干扰素-γ。对重组的敏感性变化 人类α和γ干扰素（NK细胞的激活和抗增殖 对 T 细胞的影响）和重组 IL-4 下调的敏感性 将评估 IL-2 增强的 NK 活性。证据 将寻找预激活 NK 细胞的存在（CD25 的共表达， HLA-DR 和转铁蛋白受体（Leu-19/CD16）。将执行LDA 重组人 IL-2 对淋巴细胞、NK 和 T 细胞的影响 研究 NK 祖细胞是否存在与衰老相关的转变 （细胞毒性和增殖）频率、性能水平、溶瘤 潜力、对敏感/不敏感肿瘤和主要 LAK 的亲和力 前体和效应子表型。如果有内在的问题我们会解决 区分老年人 NK 系统的免疫衰老特征是 归因于低 NK 年轻成年人口的缺失。我们会 探讨老年人的NK系统是否具有家族性。结果可能 为免疫药理学干预提供理论基础 人类老龄化、长寿的临床/基础研究的参考值 相关预测值和来自年轻/年长捐赠者的 NK 细胞克隆 未来的分子研究。

In view of higher incidence of neoplasia in the elderly, alterations in the Natural Killer (NK) cell system will be studied in healthy humans with special reference to aging. We proposed to critically examine why the NK system is hyperactive(as we have found) in a majority of healthy elderly (greater than 80 years) despite a decline in T&B cell reactivities. If IL-2 deficiency is responsible for their T cell defects, how do the NK cells escape? It is our premise that ultimate changes in cellular factors (NK effector and progenitor frequency) and/or humoral factors (lymphokines) may be responsible for these alterations. To achieve this goal, we will enumerate NK subsets (co-expression of CD2, CD8,CD11a,CD11b,&CD18 with major NK markers Leu-19,CD16, and Leu-7) and determine their contribution to the total cytolytic potential of NK cells. Plasma levels and capacity of lymphocytes to secrete IL-2 and interferon-gamma will be measured. Changes in sensitivity to recombinant human alpha and gamma IFNs (activation of NK cells and anti-proliferative effect on T cells) and sensitivity to down-regulation by recombinant IL-4 of IL-2 augmented NK activity will be assessed. Evidence for the existence of pre-activated NK cells will be sought (coexpression of CD25, HLA-DR and Transferin Receptor with Leu-19/CD16+). LDA will be performed on lymphocytes, NK and T cells with recombinant human IL-2 We will investigate if there is a senescence-related shift in NK progenitor (cytotoxic & Proliferative) frequency, performance level, oncolytic potential, affinity to sensitive/insensitive tumors and the major LAK precursor & effector phenotypes. We will resolve if there are intrinsic Immunosenescent features that distinguish the NK system in the aged is attributable to a deletion of a low-NK younger adult population. We will explore if the NK system in the elderly is familial. The results may provide a rationals for immunopharmacological interventions, basal reference values for clinical/basic studies in aging humans, a longevity- related predictive value and NK cell clones from young/old donors for future molecular investigations.