Transfer to cyclophosphamide-treated mice of natural killer (NK) cells and <i>in vivo</i> natural reactivity against tumors.

Abstract

Abstract Treatment of mice with cyclophosphamide caused marked depression in natural killer (NK) activity and in in vivo natural reactivity against i.v. challenge with radiolabeled tumor cells, and the adoptive transfer of normal spleen cells was shown to reconstitute both activities. Reactivity was measured at 2 to 8 days after treatment with cyclophosphamide (240 mg/kg i.p.) and 1 day after i.v. injection with 12.5 to 75 × 106 spleen cells. The ability of normal spleen cells to reconstitute both in vivo and in vitro natural reactivities was particularly evident when tested in mice treated with cyclophosphamide 4 days bedore, when the highest depression of natural reactivities was obtained. The effectiveness of the transfer correlated with the levels of NK activity of donor cells in a variety of situations: a. High NK-reactive spleen cells from young donors were able to reconstitute the reactivities, whereas nonreactive thymus cells were ineffective; b. High NK-reactive spleen cells from young CBA/J mice were able to partially restore the reactivities, whereas cells from low-reactive SJL/J mice were ineffective; c. Spleen cells of young CD2Fi mice, with high NK reactivity, were more effective for reconstitution than spleen cells from older mice of the same strain; d. Young mice lost their ability to transfer reactivity when their NK activity was depressed by treatment with pyran copolymer (75 mg/kg i.v.) 7 days before or with carrageenan (1 mg/mouse i.v.) 1 day before; and e. The cells responsible for the transfer of reactivity had the same characteristics as NK cells, being nonadherent, nonphagocytic, and present in nude mice, expressing asialo GM1 antigen, and lacking readily detectable Thy 1 antigen. These results demonstrate the possibility of restoring NK activity in drug-depressed animals and point to an approach for detailed analysis of in vivo regulation of NK activity and determining the role of NK cells in resistance to neoplastic cells in vivo.