Oxygen dependence of human alveolar macrophage-mediated antibody-dependent cytotoxicity

Abstract

We studied the metabolic characteristics of the human alveolar macrophage-mediated antibody-dependent cytotoxicity (ADCC) reaction, using an anti-D sensitized human erythrocyte target system. Metabolic experiments demonstrated a high resting rate of glucose metabolism in macrophages, but no oxidative metabolic burst was found to accompany the ADCC reaction. These findings were confirmed by oxygen consumption studies, showing a high resting rate of oxygen consumption by macrophages, but no change in the rate of oxygen consumption upon the addition of antibody-sensitized target cells. An anaerobic mechanism for ADCC was anticipated and investigated. Surprisingly, the macrophage-mediated ADCC reaction was found to be highly oxygen dependent. The macrophages of one chronic granulomatous disease patient were also studied and found to have a very low rate of oxidative metabolism in response to phagocytic stimuli. With oxygen present, these macrophages failed to produce significant ADCC, suggesting again that some oxidative mechanism was necessary in the macrophage-mediated ADCC reaction. Various oxygen radical scavengers were also studied. Glutathione inhibited ADCC significantly, and benzoic acid inhibited ADCC only slightly. All other scavengers had no significant inhibitory effect. Then, a known antioxidant and inhibitor of mixed-function oxidases, diethyldithiocarbamate, was found to produce a significant inhibition of the ADCC reaction. We believe this compound may be scavenging or inhibiting the production of some oxygen-dependent species important in the ADCC reaction.