CELLULAR AND CYTOKINE DEPENDENT MONOCYTE-MEDIATED LEUKEMIC-CELL DEATH- MODULATION BY INTERFERON-GAMMA AND TUMOR-NECROSIS-FACTOR-ALPHA

Activated human monocytes and macrophages are involved in host defense against neoplastic cells. In view of cellular adoptive immunotherapy, we have studied the role of tumor necrosis factor-alpha (TNF-alpha) a nd gamma-interferon (IFN-gamma) in monocyte-mediated cytotoxicity on t he level of both effector and leukemic target cells. Highly purified a nd IFN-gamma-activated monocytes were cytolytic to U937 cells up to 81 .9 +/- 5.3% (mean +/- SEM) in a 24-hour MTT cytotoxicity assay at an e ffector-to-target-cell ratio of 10. Upon IFN-gamma activation these mo nocytes showed a 20-fold increase in TNF-alpha secretion of 663 +/- 12 2 pg/mL. Comparable concentrations of recombinant human TNF-alpha show ed only cytostatic effects on U937 cells of approximately 20% after 24 hours, similar to the cytostatic effects of IFN-gamma-activated monoc yte culture supernatants. These effects could be fully reversed by ant i-TNF-alpha antibodies. U937 cells pretreated with TNF-alpha were almo st completely resistant to monocyte-mediated cytotoxicity, supernatant -mediated cytostasis and to TNF-alpha up to 10(4) U/mL. IFN-gamma-acti vated monocytes were able to lyse TNF-alpha-modified U937 cells wherea s IFN-gamma-activated monocyte supernatants showed only cytostatic act ivity after prolonged incubation. Additionally, target cell modulation by IFN-gamma potentiated the TNF-alpha-dependent cytolytic and cytost atic effects of monocytes, monocyte culture supernatants and TNF-alpha . We conclude that monocytes as a cellular component in monocyte-media ted cytotoxicity are far more potent in lysis of leukemic target cells than are secreted monokines. Furthermore, IFN-gamma and TNF-alpha are involved in the regulation of the susceptibility of leukemic cells fo r lysis by interactions with monocytes.