Natural killer cell dysfunction and apoptosis induced by chronic myelogenous leukemia cells: role of reactive oxygen species and regulation by histamine

Natural killer (NK) cells are deficient in patients with chronic myelogenou s leukemia (CML), but the mechanisms responsible for the dysfunction are no t completely understood. This study reports that CML cells effectively inhi bit the baseline and interleukin-2 (IL-2)-induced NK cell cytotoxicity agai nst a CML cell-derived line (K562), A sizable fraction of NK cells subseque ntly acquired features characteristic of programmed cell death/apoptosis, T he CML cell-mediated inhibition of NK cells required triggering of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase-mediated format ion of reactive oxygen species (ROS) and was prevented by catalase, a scave nger of ROS, and by histamine, acting via H-2-receptor-mediated inhibition of ROS production in CML cells. In contrast, nonmalignant neutrophilic gran ulocytes inhibited NK cells via ROS production without the requirement of e xogenous NADPH oxidase-triggering stimuli. We propose that paracrine produc tion of ROS may contribute to the dysfunction of NK cells in CML and that h istamine may serve as an autocrine inhibitor of ROS formation in leukemic g ranulocytes. (C) 2000 by The American Society of Hematology.