In Vitro Nonimmunologic Destruction of Cells with Abnormal Growth Characteristics by Adjuvant Activated Macrophages 1

Abstract

Discussion and Summary

In 1964 it was reported that specifically immune macrophages could destroy allogeneic target cells in vitro by a nonphagocytic mechanism (12). More recently, similar but nonimmunologic destruction of tumor target cells by activated macrophages has been described (1, 3). The present study demonstrates that activated macrophages from mice pretreated with CFA 7 weeks previously are cytotoxic to cells with abnormal growth characteristics in vitro. The results parallel those obtained with another system, activated macrophages from mice chronically infected with T. gondii (3).

The following points characterize the activated macrophage mediated cytotoxic reaction as we have observed it in this and other studies:

(1) The effector cell appears to be the activated macrophage, L cells were not destroyed by purified preparations of lymphocytes from mice whose activated peritoneal macrophages were cytotoxic to L cells or by nonactivated macrophages (3).

(2) Intimate contact between activated macrophages and target cells is apparently necessary for the cytotoxic reaction to occur. No cytopathic effect was noted when cell free medium, taken from cultures in which activated macrophages had mediated destruction of L cells, was added to L cell monolayers growing alone (3).

(3) Activation of macrophages results in increased in vitro nonspecific microbiocidal capacity for intracellular pathogens (10, 13) and in increased in vitro nonspecific cytotoxic potential for cells with abnormal growth properties (3). Furthermore, our studies show that agents which activate macrophages can stimulate nonspecific resistance to both an intracellular organism (e.g., Listeria monocytogenes) as well as neoplasia (2, 3, 9).

(4) Activation of macrophages can be effected by diverse agents, living as well as nonliving. Activation of macrophages with increased cytotoxic capabilities was stimulated in mice by chronic infection with intracellular protozoa (3), infection with an intracellular bacteria (3), and in this study with CFA.

Due to the similarity between the nonspecific resistance to neoplasia stimulated by chronic intracellular infection (2) and that stimulated by agents with properties which include immunologic adjuvant activities (9), we believe that the many agents which have been used to nonspecifically increase host resistance to tumors may operate, in part at least, through the common mechanism of stimulating activation of host macrophages with increased cytotoxic activity (3). Independently, Alexander and Evans noted macrophage mediated nonspecific destruction of tumor cells following macrophage activation with poly I:poly C and endotoxin (14). These results and our own suggest that macrophage activation can be effected nonimmu–nologically as well as develop as a by–product of a specific immunologic event.

(5) The efferent limb of the activated macrophage mediated cytotoxic reaction appears to be specific but not in an immunologic sense. The discriminatory ability of activated macrophages does not appear to be based on recognition of foreign target cell antigens but apparently on recognition of a cellular property associated with abnormal growth (3). The activated macrophage can apparently distinguish normal cells from cells with abnormal growth properties because only the latter are destroyed (3). This suggests that activated macrophage mediated cytotoxic reactions may represent a nonimmunologic mechanism of importance in the homeostatic control of abnormal cell growth in normal hosts.