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Retroviral-mediated gene transfer of gp91phox into bone marrow cells
rescues defect in host defense against Aspergillus fumigatus in murine
X-linked chronic granulomatous disease
H Bjorgvinsdottir, C Ding, N Pech, MA Gifford, LL Li and MC Dinauer
Herman B Wells Center for Pediatric Research, Department of Pediatrics
(Hematology-Oncology), James Whitcomb Riley Hospital for Children, Indiana
University Medical Center, Indianapolis, USA.
The X-linked form of chronic granulomatous disease (X-CGD), an inherited
deficiency of the respiratory burst oxidase, results from mutations in the
X-linked gene for gp91phox, the larger subunit of the oxidase cytochrome b.
The goal of this study was to evaluate the impact of retroviral-mediated
gene transfer of gp91phox on host defense against Aspergillus fumigatus in
a murine model of X-CGD. Retrovirus vectors constructed using the murine
stem cell virus (MSCV) backbone were used for gene transfer of the gp91phox
cDNA into murine X-CGD bone marrow cells. Transduced cells were
transplanted into lethally irradiated syngeneic X-CGD mice. After
hematologic recovery, superoxide production, as monitored by the nitroblue
tetrazolium (NBT) test, was detected in up to approximately 80% of
peripheral blood neutrophils for at least 28 to 35 weeks after
transplantation. Neutrophil expression of recombinant gp91phox and
superoxide production were significantly less than wild-type neutrophils.
However, 9 of 9 mice with approximately 50% to 80% NBT+ neutrophils after
gene transfer did not develop lung disease after respiratory challenge with
150 to 500 A fumigatus spores, doses that produced disease in 16 of 16
control X-CGD mice. In X-CGD mice transplanted with mixtures of wild-type
and X-CGD bone marrow, > or = 5% wild-type neutrophils were required for
protection against A fumigatus challenge. These data suggest that
expression of even low levels of recombinant gp91phox can substantially
improve phagocyte function in X-CGD, although correction of very small
percentage of phagocytes may not be sufficient for protection against A
fumigatus.
Volume 89,
Issue 1,
pp. 41-48,
01/01/1997
Copyright © 1997 by The American Society of Hematology
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