AGE-ASSOCIATED ALTERATIONS IN HUMAN NK CELL SYSTEM

鉴于老年人肿瘤发生率较高， 自然杀伤（NK）细胞系统将在健康人体中进行研究 特别是关于老化。我们建议批判性地研究为什么 NK系统在大多数健康人中是过度活跃的（正如我们所发现的 老年人（大于80岁），尽管T&B细胞减少 反应性如果IL-2缺乏是T细胞缺陷的原因， NK细胞是如何逃逸的我们的前提是， 细胞因子（NK效应子和祖细胞频率）和/或体液因子 因子（淋巴因子）可能是造成这些改变的原因。到 为了达到这个目标，我们将列举NK亚群（CD 2的共表达， CD 8、CD 11 a、CD 11b和CD 18与主要NK标志物Leu-19、CD 16和Leu-7）， 确定它们对NK总细胞溶解潜力的贡献 细胞血浆水平和淋巴细胞分泌IL-2的能力， 将测量干扰素-γ。对重组体的敏感性变化 人α和γ IFN（NK细胞活化和抗增殖 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 将寻找预活化NK细胞的存在（共表达CD 25， HLA-DR和具有Leu-19/CD 16+的转铁蛋白受体）。将进行LDA 对淋巴细胞、NK细胞和T细胞的作用 研究NK祖细胞是否存在衰老相关变化 （细胞毒性和抑制性）频率、性能水平、溶瘤 对敏感/不敏感肿瘤和主要LAK的潜在亲和力 前体和效应子表型。我们将解决，如果有内在的 免疫衰老的特点，区分NK系统在老年人是 这归因于低NK的年轻成人群体的缺失。我们将 探讨老年人NK系统是否具有家族性。结果可能 为免疫药理学干预、基础 老年人临床/基础研究的参考值，寿命- 相关的预测值和年轻/老年供体的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.