REGULATION OF MALIGNANT & NORMAL CELLS BY NK CELLS

具体目标：本申请的第一部分旨在 了解NK系统作为一种 维持造血系统内稳态的机制 避免骨髓外造血。 考虑到 NK细胞抑制骨髓中的正常祖细胞， 过度激活NK系统的可能后果可能是 骨髓功能障碍，这在男人和 将分析小鼠实验系统。 更好的 了解NK细胞抑制生长的能力， 肿瘤细胞的转移扩散是第2部分的目的，在这方面， 应用程序. MHC-1的数量变化 表达影响肿瘤的致瘤性和转移扩散 细胞将被研究。 随着知识的增长， 淋巴因子影响肿瘤敏感性以及NK细胞如何 用于过继转移模型，该研究旨在帮助 改进免疫治疗方案。 方法学：体内NK活性的慢性抑制 施用NK特异性抗体，或活化NK 细胞的急性病毒感染，将在小鼠中进行 实验系统 这些治疗的后果 多能、髓系和红系祖细胞的频率 将通过体内脾集落测定或体外测定来分析细胞 琼脂测定。 再生障碍性贫血和白细胞减少症的人将 作为可能的例子进行了分析， 包括NK细胞在内的系统可能发挥作用。 产生的因素 这些患者的淋巴细胞将被表征为纯化的， 克隆的。 对肿瘤NK敏感性的影响， MHC-1调节的致瘤性和转移扩散 通过干扰素的表达或肿瘤细胞的体内传代将被 分析了 负责赋予NK细胞 IFN-γ对肿瘤细胞的保护作用 将通过2-D凝胶和cDNA 减法 长期目标：更深入地了解生物 NK系统作为造血调节因子的重要性， 作为一种肿瘤监测机制， 控制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 免疫系统引起的骨髓炎。

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.