Systemic administration of human leukocyte interferon to melanoma patients. II. Cellular events associated with changes in natural killer cytotoxicity.

Treatment of patients with malignant melanoma with daily doses of human leukocyte interferon (IFN) resulted in natural killer (NK) cytotoxicity that increased during the 1st week of treatment and subsequently declined to pretreatment levels despite continued IFN administration; events involved in these changes were examined. The increased cytotoxicity was associated with an increased number of cells able to bind K562 targets and an increased proportion of cells able to mediate cytolysis of K562 targets. The period of increasing NK activity was also associated with an increased ability to generate in vitro cytotoxic effectors against K562 targets by stimulation with allogeneic lymphoblastoid cells. The responding cells in this system were depleted of NK activity by adherence to immune complexes. These results suggested that increased NK activity during week 1 of in vivo treatment was associated with augmentation of the development of NK cells from noncytotoxic precursors in addition to direct effects on NK cells. In contrast, the decline in NK activity appeared to be primarily a direct effect on NK cells, because these cells could no longer be augmented in vitro by additional IFN. The refractory state to IFN augmentation of cytotoxicity was limited to the period of IFN treatment in vivo, and responsiveness to IFN was promptly regained upon cessation of treatment. No evidence for the development of suppressor cells of NK effector function could be obtained.