We have investigated the natural killer (NK) activity of both fractionated (
Percoll density gradient) and unfractionated mononuclear cells from patients with
beta-thalassemia major who are
iron overloaded as a consequence of chronic transfusion
therapy. These patients were found to have significantly decreased NK activity against K562 targets at all effector:target ratios tested (p less than 0.001). Both splenectomized and nonsplenectomized patients had normal proportions of Leu-11b-staining (NK) cells. Since they had normal to elevated absolute white cell and lymphocyte counts, a change in the absolute number of NK cells could not account for the decreased killing. We also found that the decrease in NK activity was transfusion related (r = -0.603, p less than 0.005). To determine whether or not this decrease in NK activity could be related to
iron overload, we preincubated patient effector cells with
desferrioxamine (DFO) or
2,3-dihydroxybenzoic acid (DHB) for 6 hr before addition of K562 targets. Both of these
iron-chelating agents consistently increased the NK activity of cells from
thalassemia patients. DHB had the greater effect, being able to increase patient NK activity to virtually normal levels. On the other hand, preincubation of cells from normal controls with DHB caused only a slight increase in NK activity, while similar treatment with DFO had little or no effect. When target cells were preincubated with the
chelating agents before addition of either normal or patient effector cells, no change in cytotoxicity was seen, demonstrating that the
chelating agents act at the effector cell level. Furthermore, if the
chelating agents were saturated with
iron prior to preincubation with the effectors, no increase in the cytotoxicity of thalassemic NK cells was observed. These results indicate that
thalassemia patients have a reversible, transfusion-related decrease in NK function which may arise as a consequence of
iron overload.