REGULATION OF ACTIVITY IN CLONED ANTI-TUMOR LYMPHOCYTES

该建议的重点是调节生长和功能， 克隆的抗肿瘤淋巴细胞。 过去三年的实验 已经证明细胞群体的裂解活性随时间变化， 在单个细胞水平上连续的裂解效率， 而不是通过改变高溶解性/非溶解性细胞的比例。 唯一的 调节单个细胞溶解所必需的可溶性因子 白细胞介素2（IL-2）。 IL-2调节机制出现 是通过蛋白质合成的一般刺激，而不是 通过相关基因的选择性调节。 此外，我们还有 发现了淋巴细胞亚类的差异调节的证据， 不同的淋巴因子 我们将继续这些研究与克隆模型， 不同的淋巴细胞亚类。 此外，我们还将寻求类似的 在不同的活化状态下对选定的正常淋巴细胞进行的研究。 基于与多种抗原交叉反应的克隆的实验， 已经开发了一个模型的差异调节生长和溶解 通过CTL和抗原之间相互作用的亲合力产生的应答 生殖细胞 因此，弱相互作用对于刺激是最佳的 增殖，而更强的相互作用是最佳的刺激 一种溶解反应。 这种反应的差异调节允许 淋巴系统内弱抗原种类的抗原呈递 并限制了对肿瘤、感染或移植部位的溶解活性。 在 调节I类抗原的干扰素等添加因子 在靶细胞上的表达产生增加的免疫抑制剂的有效性。 在发病的解剖部位的溶解过程。 最后，我们证明了抗原特异性相互作用可以具有 对CTL生长有积极和消极的影响。 这种负面 作用似乎是对响应细胞本身的直接作用， 而不是可溶性药剂的副作用。 对增长的负面影响 是通过抗原诱导的对IL-2的无反应性。 的理解 抗原诱导的增殖阻滞的机制可能产生 关于一种诱导形式的性质的重要信息 宽容

This proposal focuses on the regulation of the growth and function of cloned antitumor lymphocytes. The experiments over the last three years have demonstrated that lytic activity of a population of cells varies over a continuum of lytic efficiency at the level of individual cells rather than by alteration of the ratio of highly lytic/non lytic cells. The only soluble factor necessary for the regulation of an individual cell's lytic capacity is interleukin 2 (IL-2). The mechanism of IL-2 regulation appears to be through a general stimulation of protein synthesis rather than through the selective regulation of relevant genes. In addition we have found evidence for the differential regulation of lymphocyte sub classes by different lymphokines. We will pursure these studies with clonal models of different lymphocyte sub classes. In addition we will pursue similar studies with selected normal lymphocytes at different states of activation. Based on experiments with clones that cross react with multiple antigens we have developed a model for the differential regulation of growth and lytic responses by the avidity of the interaction between the CTL and an antigen bearing cell. Thus a weak interaction is optimal for stimulation of proliferation while stronger interactions are optimal for the stimulation of a lytic response. This differential regulation of responses allows for antigen presentation by weak antigenic species within the lymphoid system and limits lytic activity to the tumor, infection or graft site. In addition factors such as interferon that regulate class I antigen expression on the target cell produce an increased effectiveness of the lytic process at the anatomical site of attack. Finally we demonstrate that the antigen specific interaction can have a negative as well as a positive influence on CTL growth. This negative effect appears to be a direct effect on the responding cell itself rather than a secondary effect of soluble agents. The negative effect on growth is through an antigen-induced non responsiveness to IL-2. An understanding of the mechanism of an antigen induced block in proliferation may yield important information about the nature of one form of the induction of tolerance.