AGE-ASSOCIATED ALTERATIONS IN HUMAN NK CELL SYSTEM

鉴于老年人肿瘤发病率较高， 将在健康人身上研究自然杀伤(NK)细胞系统 特别是关于老化问题。我们建议批判性地研究为什么 我们发现，大多数健康人的NK系统处于过度活跃状态 老年人(80岁以上)，尽管T&B细胞减少 反应性。如果IL-2缺乏是他们T细胞缺陷的原因， NK细胞是如何逃逸的？这是我们的前提，最终的变化 细胞因子(NK效应器和祖细胞频率)和/或体液 因素(淋巴因子)可能是导致这些改变的原因。至 为了达到这一目标，我们将计数NK亚群(CD2的共表达， CD8、CD11a、CD11b和带有主要NK标记Leu-19、CD16和Leu-7的CD18)和 测定它们对NK细胞总杀伤力的贡献 细胞。血浆水平和淋巴细胞分泌IL-2和 将测量干扰素-伽马。对重组蛋白敏感性的变化 人α和γ干扰素(激活NK细胞和抗增殖 对T细胞的影响)和对重组IL-4下调的敏感性 将评估IL-2增强的NK活性。证据表明， 将寻求存在预激活的NK细胞(CD25的共同表达， 人类白细胞抗原-DR和转铁蛋白受体与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 (细胞毒性和增殖性)频率、表现水平、肿瘤溶解 对敏感/不敏感肿瘤和主要LAK的潜在亲和力 前体和效应器表型。我们将解决是否存在内在的 区别老年人NK系统的免疫衰老特征是 可归因于NK含量低的年轻成年人口的缺失。我们会 探讨老年人NK系统是否具有家族性。结果可能是 为免疫药理学干预提供理论依据，基础 对老年人类临床/基础研究的参考值，长寿- 青年和老年献血者NK细胞克隆的相关预测价值 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.