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Blood, 15 November 2001, Vol. 98, No. 10, pp. 3097-3105
PHAGOCYTES
Reconstitution of bactericidal activity in chronic
granulomatous disease cells by glucose-oxidase-containing
liposomes
Claudia E. Gerber,
Gernot Bruchelt,
Ulrike B. Falk,
Andrea Kimpfler,
Oliver Hauschild,
Selim Kuçi,
Thomas Bächi,
Dietrich Niethammer, and
Rolf Schubert
From the University Children's Hospital, Department of
Hematology and Oncology, Tübingen, Germany; University of
Freiburg, Pharmaceutical Institute, Department of Pharmaceutical
Technology, Freiburg, Germany; and University of Zurich, Laboratory for
Electron Microscopy, Zurich, Switzerland.
Chronic granulomatous disease (CGD) is an inherited primary
immunodeficiency characterized by phagocytes devoid of a functioning nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The failure of CGD phagocytes to produce reactive oxygen species (ROS) results in a marked increase in the susceptibility of affected patients
to life-threatening bacterial and fungal infections. This study
investigated whether loading of CGD phagocytes with glucose oxidase
(GO)-containing liposomes (GOLs) could restore cellular production of
bactericidal ROS (eg, H2O2 and HOCl) in vitro.
Results indicate that GO encapsulated in liposomes enabled NADPH
oxidase-deficient phagocytes to use H2O2 for
the production of highly bactericidal HOCl. The intracellular
colocalization of bacteria and liposomes (or liposome-derived ferritin)
was demonstrated by confocal laser microscopy and electron microscopy.
After uptake of GOLs (approximately 0.2 U/mL at 1 mM total lipid
concentration, size approximately 180 nm), CGD granulocytes produced
HOCl levels comparable to those of normal phagocytes. Remarkably, after
treatment with GOLs, CGD phagocytes killed Staphylococcus
aureus as efficiently as normal granulocytes. Moreover, treated
cells retained sufficient motility toward chemotactic stimuli as
measured by chemotaxis assay. Side effects were evaluated by measuring
the H2O2 concentrations and the production of
methemoglobin in whole blood. These studies revealed that
H2O2 produced by GOLs was degraded immediately
by the antioxidative capacity of whole blood. Elevated methemoglobin levels were observed only after application of extremely high amounts
of GOLs (2 U/mL). In summary, the application of negatively charged
GOLs might provide a novel effective approach in the treatment of
patients with CGD at high risk for life-threatening infections.
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