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。 过去三年的经验 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细胞与非溶解性细胞的比例。 的 调节单个细胞的唯一必要的可溶性因子 裂解能力是白细胞介素-2（IL-2）。 IL-2的调节机制 似乎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。 另外我们 已经发现了淋巴细胞差异调节的证据 由不同的淋巴因子分类。 我们将继续进行这些研究， 不同淋巴细胞亚类的克隆模型沿着类似研究 与处于不同激活状态的所选正常淋巴细胞。 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和抗体之间的相互作用的亲合力产生应答。 携带抗原的细胞 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 刺激裂解反应。 这种反应的差异调节 允许通过细胞内的弱抗原性种类呈递抗原 淋巴系统，并限制对肿瘤、感染或移植物的溶解活性 绝佳的价钱 此外，调节I类干扰素等因子 靶细胞上的抗原表达产生增加的有效性， 在解剖学上攻击部位的溶解过程。 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， 而不是可溶性物质的副作用 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机制可能产生 关于一种诱导形式的性质的重要信息 宽容 （LB）

This proposal focuses on the regulation of the growth and function of cloned anti-tumor lymphocytes. The experiements 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 to nonlytic 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 subclasses by different lymphokines. We will pursue these studies with clonal models of different lymphocyte subclasses along with 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 atimulation 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 soIuble agents. The negative effect on growth is through an antigen-induced nonresponsiveness 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. (LB)