Natural killer cell activity and spontaneous development of lymphoma. Effects of single and multiple injections of interferon into young and aged C57BL/6 mice

Abstract

The capacity of interferon (IFN) given once or repeatedly to augment natural killer (NK) cell activity in the spleen was tested in young and aged C57BL/6 mice. Multiple injections of 10(4) u IFN i.p. into 3-month-old or 12-month-old mice did not augment cytotoxicity mediated by NK cell activity; rather it reduced this activity in relation to the effect obtained with a single injection. When T and B cells or macrophages were removed in vitro, no restoration of NK-cell activity, and therefore no suppressor cells, could be found in this system. In a long-term experiment, B6 mice were chronically injected with 10(4) u of IFN or mock-IFN from 5 months of age until death. No difference in the modification of NK-cell activity was observed after IFN and mock-IFN, regardless of the duration of treatment. However, the capacity of spleen cells to generate cytotoxic T cells after allogeneic stimulation in vitro or in vivo was increased in IFN-treated mice. The median survival time was improved by 7 weeks through treatment with IFN compared to mock-IFN, but was reduced by 9 weeks compared to the survival after treatment with saline. No significant difference in the incidence of spontaneous lymphoma resulted from IFN treatment, but the percentage of tumors observed in mice receiving mock-IFN (68.1%) was higher than that in mice receiving saline (44.1%). These results indicate that, while a stimulating effect resulting in a delay in mortality and in tumor development can be attributed to IFN itself, the contaminating antigenic products are plausibly responsible for the deleterious effect of the total preparation.

Development of hyporesponsiveness of natural killer cells to augmentation of activity after multiple treatments with biological response modifiers

“…The development of hyporesponsiveness resulting from multiple treatments with two BRMs, IFN, and MVE-2 [3,17,20,22], prompted us to test whether hyporesponsiveness would also occur with other BRMs that have been reported to augment NK-cell activity following a single treatment. Because of the possible important role of NK cells and macrophages in resistance to metastases and in BRM-mediated antitumor therapy [1,11,13,27], it was important to analyze the mechanism of hyporesponsiveness of NK activity that might be induced by BRMs and also to determine whether such hyporesponsiveness occurs with M0 activity.…”

“…However, recent phase-I clinical studies [17,20] and a preclinical study [3] indicate that multiple treatment with interferon (IFN) failed to boost NK activity. Similarly, while several different molecular weight maleic anhydride divinyl ethers (MVE) have been shown to significantly augment NK-cell-activity [1], we recently reported that multiple treatments with a low-molecular-weight MVE-2 led to the development of hyporesponsiveness to augmentation of NK-cell activity [22].…”

“…Natural killer (NK) and macrophage (M0) tumoricidal activity have been reported to be augmented with several chemical and biological agents (biological response modifiers, BRMs) [10] which have shown some antitumor prophylactic or therapeutic efficacy in animal tumor systems [1,3,5,9,22,27]. For optimal therapeutic efficacy, sustained or repeated augmentation of effector cell function would probably be needed.…”

Augmentation of Organ-Associated NK Activity by BRMs: Association of NK Activity with Mononuclear Cell Infiltration

“…The ability of BRMs to augment NK activ ity in nonlymphoid organs provided a basis for investigating previous observations that the repeated administration of IFN during preclinical [67] or clinical trials [68. 69] or MVE-2 to mice [57,58,70] resulted in a hyporesponsiveness of NK activity in blood and/or in spleen.…”