ACTIVATED MACROPHAGES AS CYTOTOXIC EFFECTOR CELLS

Abstract

High levels of BCG remain localized in the anatomical compartment(s) into which it was administered. The presence of cytotoxic activated macrophages in the tissues is a local phenomenon confined to anatomical compartments that contain high levels of inducing antigen. The in vivo expression of nonspecific resistance to S[sarcoma]180 growth in the peritoneal cavity correlates with the presence of high levels of heterologous inducing antigen (BCG) and activated peritoneal macrophages with nonspecific cytotoxic effect for tumorigenic cells in vitro. Cytotoxic activated macrophages remain in the tissues for a prolonged period of time if the antigen which induced their mobilization persists (e.g., BCG or toxoplasma). The rejection of allogeneic L1210 luekemia cells in specifically immunized CBA mice produces activated macrophages with nonspecific cytotoxic effects for tumorigenic cells. The population of cytotoxic activated macrophages is confined to the anatomical compartment containing the L1210 allograft. Macrophages rapidly revert to normal when the antigen which induced their mobilization (allogeneic L1210 cells) is cleared from the tissues and are not cytotoxic in vitro for 3T12 fibroblasts which share common H-2 antigens with the L1210 cells. In nonspecific tumor cell destruction, the cytotoxic activated macrophages induced by a heterologous antigen (e.g., BCG or toxoplasma) are present in the tissues before grafting the S180 cells and can still be detected after the S180 cells are rejected. This is because the specific antigen (e.g., BCG or toxoplasma) which induced the production of cytotoxic activated macrophages remains in the tissues. The persistence of inducing antigen (and cytotoxic activated macrophages) in the tissues after the tumor cells are destroyed seems to characterize nonspecific as opposed to specific tumor resistance. Because activated macrophages lose their cytotoxic activity after a period of in vitro culture, a need for the continuous interaction of specific antigen and sensitized lymphocytes can be demonstrated for the maintenance of functional macrophage activation. The ability of trypan blue to inhibit nonspecific and specific tumor resistance in vivo, as well as the cytotoxic activities of activated macrophages in vitro, is evidence for a significant role for activated macrophages as cytotoxic effector cells.