Abstract
Chronic granulomatous disease (CGD) is a genetic disorder characterized by recurrent bacterial and fungal infections and tissue granuloma formation. CGD phagocytes are unable to generate superoxide because of mutations in any of four proteins of the phagocyte NADPH oxidase. Prophylactic recombinant human interferon-γ (IFN-γ) has been shown to reduce the frequency and severity of infections in CGD patients, but its mechanism(s) remains undefined, and its benefit has been questioned. We investigated the prophylactic effect of IFN-γ in the mouse model of the major autosomal recessive(p47 phox ) form of CGD. In a prospective, randomized, placebo-controlled study, we compared IFN-γ, 20,000 U administered subcutaneously (s.c.) three times weekly, to placebo in 118 p47 phox-/- mice. By 6 weeks of study, there were 3 infections in the IFN-γ group compared with 13 infections in the placebo group (77% reduction in infections, p<0.01). By 18 months of study, there were 7 infections in the IFN-γ group compared with 18 infections in the placebo group (39% reduction in infections, p<0.01). Two animals receiving IFN-γ had seizures after 7 months in the study. No other toxicities were observed. Peripheral blood phagocytes from IFN-γ treated p47 phox-/- mice produced no superoxide, excluding restoration of the oxidative burst as a mechanism for the IFN-γ effect. There were no differences in either peritoneal macrophage nitrate production or thioglycollate-induced peritoneal exudate between treatment groups. This animal model demonstrates a prophylactic benefit of IFN-γ similar to that seen in humans and provides an opportunity to investigate the mechanism(s) of action for IFN-γ in CGD.
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