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Prolonged recombinant interferon-gamma therapy in chronic granulomatous
disease: evidence against enhanced neutrophil oxidase activity
RC Woodman, RW Erickson, J Rae, HS Jaffe and JT Curnutte
Department of Molecular and Experimental Medicine, Scripps Research
Institute, La Jolla, CA.
Recombinant interferon-gamma (rIFN-gamma) therapy has become an effective
form of prophylaxis for patients with chronic granulomatous disease (CGD).
Preliminary studies with CGD suggested that rIFN-gamma treatment enhanced
phagocyte oxidase activity and increased superoxide (O2-) production. We
evaluated several aspects of neutrophil NADPH oxidase activity in 19 CGD
patients (representing all four known types of CGD) receiving prolonged
rIFN-gamma therapy (6 to 27 months). In contrast to earlier studies, we
failed to detect any improvement in neutrophil NADPH oxidase activity in 18
of the 19 CGD patients as determined by (1) intact cell O2- production
(continuous assay), (2) nitroblue tetrazolium (NBT) staining, (3)
cytochrome b558 spectroscopy, and (4) activity levels of cytosol and
membrane oxidase components using a cell-free activation system. One
patient with a variant form of X-linked CGD had a transient increase in
neutrophil O2- production following 3 months of rIFN-gamma therapy.
However, this was not sustained, and was not associated with any change in
cytochrome b levels. In some patients, rIFN-gamma therapy was associated
with the appearance of a small subset of circulating monocytes (1% to 20%)
that were NBT-positive. Although the functional significance of this
monocyte subpopulation needs to be determined, these results suggest that
one possible mechanism by which rIFN-gamma may benefit CGD patients is by
partially correcting the respiratory burst defect in a subset of monocytes.
We conclude that the clinical benefit of prolonged rIFN-gamma therapy in
the vast majority of CGD patients is not due to enhanced neutrophil NADPH
oxidase activity. The mechanism of action of rIFN-gamma in most CGD
patients remains unknown.
Volume 79,
Issue 6,
pp. 1558-1562,
03/15/1992
Copyright © 1992 by The American Society of Hematology
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