REGULATION OF ACTIVITY IN CLONED ANTI-TUMOR LYMPHOCYTES

这项建议的重点是对生长和功能的调节 克隆的抗肿瘤淋巴细胞。过去三年的实验 已经证明了一群细胞的裂解活性在不同的 在单个细胞水平上的裂解效率的连续体 而不是通过改变高度溶解/非溶解细胞的比率。唯一的 调节单个细胞裂解所需的可溶性因子 能力是白介素2(IL-2)。IL-2的调节机制出现了 通过蛋白质合成的一般刺激，而不是 通过对相关基因的选择性调控。此外，我们还有 发现淋巴细胞亚类的差异调节的证据 不同的淋巴因子。我们将用克隆模型纯化这些研究 不同的淋巴细胞亚类。此外，我们还将追求类似的 选择处于不同激活状态的正常淋巴细胞进行研究。 基于与多种抗原发生交叉反应的克隆的实验，我们 为生长和裂解的不同调控开发了一个模型 CTL与抗原相互作用亲和力的反应 承重细胞。因此，弱相互作用对于刺激 增殖，而更强的相互作用是刺激的最佳选择 一种抒情的反应。这种对反应的不同调节允许 淋巴系统内弱抗原性物种的抗原提呈 并将裂解活性限制在肿瘤、感染或移植物部位。在……里面 如干扰素等调节I类抗原的附加因子 在靶细胞上的表达产生了增加的有效性 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有一个 对CTL生长既有积极影响，也有消极影响。这张底片 效应似乎是对反应细胞本身的直接影响，而不是 而不是溶解药剂的次要作用。对增长的负面影响 是通过抗原诱导的对IL-2的无反应。一种理解 抗原诱导的增殖阻断的机制可能会产生 关于一种形式的归纳的性质的重要信息 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.