REGULATION OF MALIGNANT & NORMAL CELLS BY NK CELLS

具体目标：此应用程序的第一部分旨在 理解NK系统作为一种 维持造血系统内环境平衡的机制 并避免额外的骨髓造血。鉴于……的能力 NK细胞抑制骨髓中的正常祖细胞， NK系统过度激活的可能后果可能是 骨髓功能障碍，以及人类和 将对小鼠实验系统进行分析。更好的 对NK细胞抑制生长的能力的了解 肿瘤细胞的转移性扩散是本文第二部分的目标 申请。MHC-1数量变化的可能性 表达影响肿瘤的致瘤性和转移扩散 将对细胞进行调查。随着越来越多的人了解如何 淋巴因子影响肿瘤敏感性以及NK细胞如何 在收养迁移模型中使用，这项研究旨在帮助 完善免疫治疗方案。 方法学：体内慢性抑制NK活性 注射NK特异性抗体或激活NK 细胞经急性病毒感染后，将在小鼠身上进行 实验系统。这些治疗的后果是 多能、髓系和红系祖细胞的频率 细胞将通过体内脾集落试验或体外试验进行分析 琼脂分析。人类的再生障碍性贫血和白细胞减少症 作为免疫的条件的可能的例子被分析 包括NK细胞在内的系统可能起到一定作用。由以下因素产生的因素 这些患者的淋巴细胞将被鉴定为纯化和 克隆的。对肿瘤NK敏感性的影响， MHC-1基因调控的致瘤性和转移扩散 通过干扰素表达或体内传代的肿瘤细胞 分析过了。与NK产生有关的蛋白质和基因 干扰素-γ对肿瘤细胞的保护作用 治疗将通过二维凝胶和cDNA进行研究 减法。 长期目标：更深入地了解生物 NK系统作为造血和免疫调节因子的意义 作为一种肿瘤监测机制，将有可能在 受控方式上调或下调宿主NK活性。这 可能会对患者的治疗产生积极的影响 患有恶性肿瘤或骨功能障碍 由免疫系统引起的骨髓。

Specific aims: The first part of this application aims at understanding the biological significance of the NK system as a mechanism to maintain homeostasis in the hematopoietic system and to avoid extra medullary hematopoiesis. Given the ability of NK cells to inhibit normal progenitor cells in the bone marrow, possible consequences of an over-activated NK system may be dysfunction of the bone marrow, and example of this in man and mouse experimental systems will be analyzed. A better understanding of the ability of NK cells to inhibit growth and metastatic spread of tumor cells is the aim of part 2 in this application. The possibility that quantitative variations of MHC-1 expression affects tumorogenicity and metastatic spread of tumor cells will be investigated. With increased knowledge about how lymphokines affect tumor sensitivity and how NK cells can be used in adoptive transfer models, the study aim at helping to improve immunotherapy protocols. Methodology: Chronic suppression of NK activity by in vivo administration of NK - specific antibodies, or activation of NK cells by acute virus infection, will be performed in mouse experimental system. The consequences of these treatments on the frequency of pluripotent, myeloid and erythroid progenitor cells will be analyzed by in vivo spleen colony assays or in vitro agar assays. Aplastic anemia and leukopenia in man will be analyzed as possible examples of conditions where the immune system, including NK cells may play a role. Factors produced by lymphocytes of these patients will be characterized purified and cloned. The consequences on tumor NK sensitivity, tumorogenicity and metastatic spread of modulation of MHC-1 expression by interferons or in vivo passage of tumor cells will be analyzed. The proteins and genes responsible for confering NK protection to tumor cells as a consequence of IFN-gamma treatment will be investigated by 2-D gels and by cDNA subtraction methods. Long-term objectives: A deeper understanding of the biological significance of the NK system as a regulator of hematopoiesis and as a tumor surveillance mechanism will make it possible to in a controlled manner up- or down-regulate host NK activity. This may have positive consequences in the therapy of patients suffering from malignant tumors or from dysfunction of the bone marrow caused by the immune system.