The macrophage as an antineoplastic surveillance cell: biological perspectives.
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Biomedical subjects
Publications and source records attributed to J B Hibbs.
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The tumoricidal capabilities of macrophages can be reversibly inhibited by a lipoprotein of high molecular weight, and the inhibition appears to be reproduced by enrichment of macrophage plasma membranes with cholesterol. A second serum component of lower molecular weight enhances macrophage cytotoxicity. The presence of these components in normal serums suggests a physiological role for such factors in the regulation of macrophage function.
Tumor killing by activated macrophages is not a highly determined biologic event, but a relative capability influenced by the local environment. An intrinsic macrophage cytotoxic effector system is modulated by serum and other environmental factors that can either enhance or suppress tumor killing. Activated macrophages kill tumor cells only when a regulating threshold drops to a critically low level.
It has been reported that trypan blue treatment decreases the nonspecific resistance of mice to transplanted tumors and inhibits the in vitro cytotoxic activity of activated macrophages. We wished to determine whether this effect of trypan blue could be due to a selective inhibition of certain macrophage functions or whether it reflected a broader form of immunosuppression. We therefore tested the effects of trypan blue on a variety of immunological responses. Treatment of mice with trypan blue delayed their rejection of skin allografts and transplants of a highly antigenic syngeneic ultraviolet light-induced tumor. Trypan blue treatment of either donor or recipient decreased the local graft-versus-host reaction. Filtration of lymph node cells from trypan blue-treated donors on a nylon wool column before use in the graft-versus-host assay abrogated the depressive effect of trypan blue. A transient reduction in the blastogenic response of spleen cells to concanavalin A and lipopolysaccharide mitogens was observed after a single injection of trypan blue, but the response of lymph node cells was unaffected. The depressed response of splenic lymphocytes was not entirely reversed by removal of adherent cells. The primary and secondary hemagglutinin responses to sheep erythrocytes were unaffected in trypan blue-treated mice, and the proportion and phagocytic activity of thioglycolate-induced peritoneal macrophages were also unaltered. We conclude that treatment of mice with trypan blue selectively inhibits certain macrophage functions but, at high doses, it can also inhibit some lymphocyte activities.
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The cytotoxic activity of activated macrophages against tumorigenic target cells appears to be mediated by lysosomal enzymes of activated macrophage origin. Lysosomes of activated macrophages are secreted directly into the cytoplasm of susceptible target cells, which subsequently undergo heterolysis. This reaction can be inhibited by agents which prevent the exocytosis of macrophage lysosomes (hydrocortisone) or which interfere with the action of lysosomal enzymes (trypan blue).
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Activated mouse macrophages were not cytotoxic to contact-inhibited nontumorigenic 3T3 fibroblasts, but caused marked destruction to non-contact-inhibited, tumorigenic 3T12 and simian virus 40-transformed fibroblasts. Nonimmunologic recognition and destruction of target cells by activated macrophages is independent of altered morphology, abnormal karyotype, and ability for continuous multiplication in vitro-all characteristics of 3T3 fibroblasts. A modification e f the target cell surface that results in a high in vitro saturation density, agglutinability by plant lectins, and tumorigenicity appears to evoke a cytotoxic response by activated macrophages.
Cytotoxic activity of activated mouse macrophages against mouse embryo fibroblasts was tested before and after spontaneous transformation of the fibroblasts in vitro. Activated macrophages caused little or no destruction of untransformed fibroblasts but were markedly cytotoxic to the same fibroblasts after spontaneous transformation. The efferent limb of this cytotoxic reaction appears to be nonimmunologic and to be related to abnormal growth properties rather than to the antigenic composition of target cells.
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