Lefever R, Hiernaux J, Urbain J, Meyers P
Service de Chimie Physique, Université Libre de Bruxelles, Belgium.
Bull Math Biol. 1992 Sep;54(5):839-73. doi: 10.1007/BF02459933.
Using the chromium release assay and the single cell assay in agarose, we study the cytotoxic reaction of the MHC-restricted T lymphocyte clones P89:15 and P1:3, which recognize distinct but specific tumour antigens on the surface of syngeneic P815 mastocytoma cells. We propose a mathematical model which describes these experiments, accounts for the strongly non-Michaelian behaviour of the reaction and permits us to estimate the kinetic parameters characterizing effector-target conjugation and lethal hit delivery. The results show that the binding and lytic activity of effector cells is modulated by the number of targets bound to them. The binding of a second target by an effector having already a target bound is facilitated; on the other hand, an effector having bound two targets delivers a lethal hit more slowly than one with a single target bound. We investigate the role of these kinetic properties in the competition between the process of tumour progression due to cancer cell replication and the process of tumour regression due to T lymphocyte cytotoxic activity. For both clones, we estimate the effector-target ratio beyond which rejection prevails. This ratio is nine times larger for P1:3 than for P89:15. Furthermore, our analysis suggests that there exists an optimal specificity minimizing this ratio. Deviations from this optimum, be it in the sense of an increase or decrease of specificity, tends to stabilize the tumoural state: a situation which in the broader context of the immune response evolution and regulation can be viewed as an immune response dilemma.
我们使用铬释放试验和琼脂糖中的单细胞试验，研究了MHC限制的T淋巴细胞克隆P89:15和P1:3的细胞毒性反应，这些克隆识别同基因P815肥大细胞瘤细胞表面不同但特定的肿瘤抗原。我们提出了一个数学模型来描述这些实验，解释反应强烈的非米氏行为，并使我们能够估计表征效应细胞与靶细胞结合及致死性打击传递的动力学参数。结果表明，效应细胞的结合和裂解活性受与其结合的靶细胞数量的调节。已经结合了一个靶细胞的效应细胞更容易结合第二个靶细胞；另一方面，结合了两个靶细胞的效应细胞比只结合了一个靶细胞的效应细胞传递致死性打击的速度更慢。我们研究了这些动力学特性在癌细胞复制导致的肿瘤进展过程与T淋巴细胞细胞毒性活性导致的肿瘤消退过程之间竞争中的作用。对于这两个克隆，我们估计了排斥反应占优势的效应细胞与靶细胞比例。P1:3的这个比例比P89:15大九倍。此外，我们的分析表明存在一个使该比例最小化的最佳特异性。偏离这个最佳值，无论是特异性增加还是减少，都倾向于使肿瘤状态稳定：在免疫反应进化和调节的更广泛背景下，这种情况可被视为一种免疫反应困境。
