Effect of IFN-γ on Innate Immune Cells

Named for their potent ability to interfere and protect against viral infections, interferons (IFNs) have many regulatory effects on the immune system.1 Of the members of the two classes of these compounds, IFN-γ has the most diverse and powerful immune effects. Studies have mostly evaluated IFN-γ interactions with cells of adaptive immunity, including macrophages and lymphocytes. Effects on innate immunity, particularly polymorphonuclear leukocytes or neutrophils and monocytes are less well studied. However, investigations have suggested that IFN-γ may be involved in signal transduction, gene expression, the respiratory burst and neutrophil NADPH oxidase (Nox2) activity, phagocytosis, motility, microbicidal activity, and apoptosis. Not all of these functions are enhanced by IFN-γ; but the clinical use of this cytokine has been driven, in part by these results. For example, the primary motivation for initiating investigation of its beneficial clinical effects in Chronic Granulomatous Disease (CGD) was its effects on Nox2 activity.2 Most data in this area was based on studies using differentiated neutrophils from peripheral blood.1 However, the phenotype of neutrophils developed under the influence of this cytokine, not just changes expressed by exposure of differentiated cells to IFN-γ, is critical to understanding the physiologic effects of IFN-γ and the broad applications for its use in treatment of a range of human diseases. To expand their understanding of the role of IFN-γ in the development and functional integrity of the neutrophil, the investigators have completed a series of studies with PLB-985 cells in an in vitro culture system of myeloid cells. In this proposal, the investigators will evaluate innate immune activation and phagocyte function in healthy adult volunteers who are receiving IFN-γ.