On the kinetics and optimal specificity of cytotoxic reactions mediated by T-lymphocyte clones

Abstract

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.

Natural cytotoxic cells of gilthead seabream: maximum percentage of lysis

“…In mammals, the cytotoxic process is known to NATURAL CYTOTOXIC CELLS OF GILTHEAD SEABREAM proceed through a series of associated steps: e#ector-target cell binding, e#ector lethal hit delivery, target cell lysis and disintegration [14]. The whole process or each of the individual steps can be characterised from their kinetic parameters, some of which have been determined for systems formed of mammalian e#ector-target cells [1,2,8,9]. These parameters are very useful tools for studying the e#ect of di#erent modulators, such as divalent cations, temperature, specific antibodies, cytokines or pharmacological agents, on the cytotoxic response [9].…”

“…Another model estimates the kinetic parameters of each step of the cytotoxic process and considers their influence on the whole process at the single cell or population level [8,9,15].…”

“…Final NCC activity was calculated as follows: Cytotoxic activity (%)=100 (% sample % control )/(100 % control ). ) of gilthead seabream head-kidney leucocytes against tumour cells was determined using the standard procedure used by Lefever et al [9]. For this, the fraction of targets lysed up to time t, …”

“…The most widely used method has been the Michaelis-Menten approximation [1][2][3][4], although the Hill equation for allosteric kinetics has also been applied [5,6]. Other studies have taken into account not only the kinetics of the overall process, but the kinetics of each one of the stages at single cell or population level [7][8][9].…”

A Feedback Control Model of Comprehensive Therapy for Treating Immunogenic Tumours

“…Much attention has been paid to the interactions between the immune system and a growing tumour in [Angelis et al, 2003;De Pillis & Radunskaya, 2003;Bodbar & Bodbar, 2003;Karen & Jonathan, 2005;Lefever et al, 1992;Look et al, 1981;Salleem & Angrawal, 2012;Subuyanto et al, 2014]. With models such as those described in these papers numerical estimates of biologically significant parameters have been obtained and interesting phenomena interpreted.…”