EFFECT OF CYTOKINES IN HOST DEFENSE AND INFLAMMATION

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The purpose of this project is to study effects of cytokines upon host defense and upon phagocytic cell function. Interferon gamma (IFN-g) corrected abnormal oxidative metabolism and bactericidal and fungicidal activity of neutrophils and monocytes from patients with chronic granulomatous diseases of childhood (CGD) whether administered in vivo or in vitro. 127 CGD patients (27 at NIH) were entered into a double blinded study of the efficacy of every other day prophylactic IFN-g (0.05 mg/square-meter) in preventing infection. IFN-g administration decreased the incidence of infection by 70% and decreased hospital days for those infections which did occur. Normal monocytes treated in vitro with IFN-g increased mRNA transcripts and protein levels of membrane and cytoplasmic NADPH oxidase components, while Interleukin 4 (IL-4) markedly decreased these components. The p47-phox oxidase component increased or decreased more than other components, indicating that this component is most critical in cytokine regulation of oxidase activity. IFN-g can induce differentiation of HL-60 myeloid leukemia cells with acquisition of oxidase capacity. During such differentiation the most dramatic increase was seen with p47-phox, while p67-phox appeared most slowly. In other studies B-cells from patients with Hyperimmunoglobulin E and Recurrent Infections (Job's) Syndrome (HIE) were shown to have abnormally high spontaneous in vitro synthesis of IgE which was decreased by administration of IFN-g in vitro or in vivo. Production of IgG1,3, and 4, but not IgG2 or IgM was also decreased by IFN-g. In other studies CGD monocytes in vitro formed granulomas and these granulomas could be dispersed with steroids.