Angela Santoni

In vivo reactivity of mouse natural killer (NK) cells against normal bone marrow cells

Abstract An in vivo role for mouse natural killer (NK) cells in the rapid rejection of transplantable tumors has been previously demonstrated, using an assay of elimination of [125I]iododeoxyuridine-labeled tumor cells from the lungs and other organs. We have now used the same technique to examine the role of NK cells in in vivo clearance of syngeneic or allogeneic bone marrow cells from normal mice. The degree of clearance from the lungs or liver, at 4 hr after intravenous inoculation of radiolabeled bone marrow cells, correlated with the levels of NK activity in the recipients. Young CBA mice, with high NK activity, showed substantially more clearance of bone marrow cells than SJL mice, with low NK activity. Within the same strain, mice at 7 weeks of age had higher in vivo as well as in vitro reactivity than did 30-week-old mice. These differences were seen with syngeneic bone marrow cells, but there was stronger in vivo reactivity against parental cells by F1 hybrid recipients. Depression of NK activity by pretreatment of mice with cyclophosphamide, silica, or carrageenan also caused decreased clearance of syngeneic or parental bone marrow cells. Conversely, augmentation of NK activity by pretreatment of the mice with polyinosine:polycytidine resulted in increased in vivo clearance. These results indicate that NK cells may be involved in the in vivo control of growth of some normal cells as well as of some tumor cells.

Adriamycin-induced antitumor response in lethally irradiated mice

Lethally irradiated mice pretreated with a wide range of Adriamycin (ADM) doses were tested for their in vivo antitumor response against transplanted lymphoma cells. Tumor growth, as assessed by 125IUdR uptake, was markedly impaired by treatment with ADM by a variety of different administration schedules. This ADM-induced antitumor response was largely dose-dependent, occurred regardless of route of administration, and was detectable as late as 15-30 days following drug treatment. No genetic restriction could be found to regulate the development of this response, since tumor growth inhibition occurred in syngeneic as well as allogeneic tumor-host combinations. ADM-induced antitumor response did not appear to be due to direct antitumor action by the drug, but rather to some interaction with host immune mechanisms. Antimacrophage agents, such as silica or carrageenan, abrogated the response. The possible implication of different cells as effectors of this response is discussed.

Regulation of Natural Killer Cell Activity

Natural killer (NK) cells have cytotoxic activity against a variety of tumor cells and also against some microorganisms or cells infected by microbial agents (for comprehensive review and detailed information, see Herberman and Holden, 1978, and Herberman, 1980, 1982). They may thereby serve as important effector cells in host resistance against disease. NK cells are present in virtually all individuals and can be activated rapidly by a wide variety of stimuli, and their activities do not depend on sensitization by antigens and the development of specific immune responses. Thus, these cells may function as a first line of defense against attack by neoplastic cells or infectious agents.

REGULATION OF IN VIVO REACTIVITY OF NATURAL KILLER (NK) CELLS

Publisher Summary This chapter focuses on regulation of in vivo reactivity of natural killer (NK) cells. The results with normal bone marrow cells are consistent with previous indications that NK cells mediate in vivo natural resistance against bone marrow transplants but differ in that some reactivity has been found against syngeneic cells and the stronger reactivity of allogeneic or parental cells, suggesting an autoreactive nature of NK cells. In view of the accumulating evidence for a possible in vivo role of NK cells in defenses against tumor cells, virus infections, and in homeostatic regulation of normal nonneoplastic tissues, it is particularly important to develop procedures to more definitively document their in vivo importance and to determine how to manipulate the levels of in vivo natural reactivity. The suppressor cells present in the spleen of normal SJL/J mice could account for the lower reconstitution of such mice and for the low NK activity of this strain. The data support the in vivo relevance of in vitro defined suppressor cells for NK activity.