(Journal of Leukocyte Biology. 2001;70:868-872.)
© 2001
by Society for Leukocyte Biology
In vivo GM-CSF prevents dexamethasone suppression of killing of Aspergillus fumigatus conidia by bronchoalveolar macrophages
Elmer Brummer*,
Anjum Maqbool* and
David A. Stevens*
* California Institute for Medical Research and
Division of Infectious Diseases, Department of Medicine, Santa Clara Valley Medical Center, San Jose, and
Stanford University School of Medicine, Stanford, California
Correspondence: Dr. Elmer Brummer, Div. of Infectious Diseases, Dept. of Medicine, Santa Clara Valley Medical Center, 751 S. Bascom Ave., San Jose, CA 95128-2699. E-mail: e.brummer{at}juno.com
 |
ABSTRACT
|
|---|
Dexamethasone (DEX) is a potent immunosuppressive agent used in
the treatment of several disorders. However, despite its beneficial
effects, DEX puts patients at risk for opportunistic infections,
especially pulmonary aspergillosis. Previously we reported that in
vitro granulocyte-macrophage colony-stimulating factor (GM-CSF) blocks
the immunosuppressive action of DEX on bronchoalveolar macrophages
(BAMs). Here we report that BAMs freshly isolated from mice treated
intraperitoneally with DEX for 24 h had significantly
(P<0.01) reduced killing of conidia, i.e., 15 ± 5%
conidia killed by BAMs from DEX-treated mice versus 35 ± 3% by
BAMs from mice given saline, 38 ± 5% by BAMs from mice given
GM-CSF, and 39 ± 1% by BAMs from mice given both DEX and GM-CSF.
On the other hand, in another compartment GM-CSF could not block the
DEX reduction of spleen weight and spleen cellularity. Unlike
GM-CSF, granulocyte colony-stimulating factor did not block
DEX suppression of BAMs. GM-CSF given 24 h before DEX resulted in
blocking of DEX suppression of BAM conidiacidal activity. However, when
DEX was given 24 h before GM-CSF, DEX suppression of BAM was not
reversed. These data show that GM-CSF in vivo blocks the in vivo
immunosuppressive effects of DEX on BAM killing of conidia and suggest
a potential use of GM-CSF in patients at risk for aspergillosis due to
immunosuppressive DEX treatment.
Key Words: alveolar macrophages • conidia • glucocorticoids
|
INTRODUCTION
|
|---|
Airborne conidia of Aspergillus species, especially
Aspergillus fumigatus, are ubiquitous in the environment and
pose a risk for pulmonary infection in a variety of immunocompromised
hosts, including patients immunosuppressed by corticosteroids
[1
, 2
] or patients with Cushing’s syndrome
[3
, 4
]. Once infection is established, it
is highly lethal [5
, 6
] and remains high
despite improvements in diagnosis and new antifungal drugs
[6
]. Although efforts have been made to reduce the risk
of exposure, such as the use of air filtration, effective prophylaxis
is being sought, particularly for neutropenic patients with
antifungal agents and immunomodulation.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) not only
stimulates production of cells of the granulocyte and macrophage
lineages but also enhances the functional activities of neutrophils,
monocytes, and macrophages [7
, 8
]. GM-CSF
has been reported to interfere in vitro with dexamethasone (DEX)
suppression of human monocyte antifungal activity against hyphae of
A. fumigatus [9
, 10
] and killing
of conidia by murine peritoneal and bronchoalveolar macrophages (BAMs)
[11
]. However, in vitro treatment of spleen cells with
GM-CSF has failed to interfere with DEX suppression of spleen
cell-proliferative responses to the mitogen concanavalin A
[11
]. This suggests that GM-CSF might prevent unwanted
effects of DEX on macrophages but would not interfere with desired DEX
suppression on lymphocyte responses.
Here we report our investigation of the effects of in vivo treatment
with DEX, GM-CSF, or both DEX and GM-CSF on ex vivo ability of BAMs to
kill conidia of A. fumigatus.
|
MATERIALS AND METHODS
|
|---|
Reagents
DEX (4 mg/mL) used for injection in these experiments was from
American Reagent Laboratories, Shirley, NY. Recombinant murine (rm)
GM-CSF was from Immunex, Seattle, WA. Optimal colony-forming activity
was at 10 to 100 ng/mL of GM-CSF, and 1 µg/mL was equivalent
to 2,000 IU/mL. rmGM-CSF from Endogen (Woburn, MA) gave the same
results (data not shown), and these reagents could be used
interchangeably. Recombinant human (rh) granulocyte colony-stimulating
factor (G-CSF) was from R&D Systems, Minneapolis, MN, and studied at
the same milligrams-per-kilogram dose as GM-CSF. Human G-CSF is active
on murine cells and in vivo in the mouse [12
]. (2,3-bis
[2-methoxy-4-nitro-5 sulfophenyl]-2H-tetrazolium-5-carboxanilide)
(XTT) and coenzyme Q (2,3-dimethoxy-5-methyl-1,4-benzoquinone) were
obtained from Sigma Chemical Co., St. Louis, MO.
In vivo treatment
In simultaneous treatment protocols, groups of 8–10-week-old
CD-1 male mice (Charles River Laboratories, Hollister, CA) were treated
intraperitoneally (i.p.) with saline (0.2 mL/mouse), DEX, rmGM-CSF (0.5
µg/mouse), or DEX + rmGM-CSF. In preliminary dose-finding
studies, DEX doses of 0.8–1.2 mg/mouse were studied. Because the
dose-response curve was flat in that range, a dose of 0.8 mg was
selected for further studies. In one experiment mice were treated with
saline, DEX (0.8 mg/mouse), rhG-CSF (0.5 µg/mouse), or DEX +
rhG-CSF. This dose of G-CSF is biologically active in vivo, stimulating
neutrophils and tissue macrophages [13
].
In one sequential treatment protocol, groups of mice first were given
saline or 0.5 µg of rmGM-CSF (Endogen) i.p. and 24 h later were
given DEX (0.8 mg/mouse) or saline i.p. The reverse protocol consisted
of giving DEX (0.8 mg/mouse) or saline first and 24 h later giving
an injection i.p. with 0.5 µg/mL of rmGM-CSF (Endogen) or saline. In
all cases BAMs were collected and tested 24 h after the last
treatment.
BAMs
BAMs were obtained from lungs of mice by lavage with
phosphate-buffered saline + 10% fetal bovine serum (FBS) +
0.1% EDTA (pH 7.2) as previously described by our laboratory
[14
]. BAMs at 106/mL of RPMI-1640 +
10% FBS were plated at 0.1 mL per microtest plate well [Costar,
Corning, NY (catalog no. 3696)]. Cultures were incubated for 2 h
at 37°C in 5% CO2 + 95% air, and nonadherent cells
were aspirated. Adherent cells constituted the BAM monolayer. Each
experiment had quadruplicate wells for each experimental condition
studied.
Aspergillus fumigatus
A clinical isolate of A. fumigatus, AF-10, was from
the culture collection at the Infectious Diseases Research Laboratory,
California Institute for Medical Research, San Jose. AF-10 was grown on
Sabouraud dextrose agar (SDA) at 35°C until abundant conidia were
produced. Conidia were collected in distilled water, filtered through
gauze, counted, and suspended in RPMI-1640 + 10% FBS + 10%
fresh mouse serum to the desired inoculum concentration. Over 95% of
the inoculum consisted of single conidia.
Killing assay
Short-term assays allowed assessment of killing. A 2.5-h assay
was used to measure conidiacidal activity [15
].
Monolayers of BAMs were challenged with approximately 103
conidia/well and incubated at 37°C for 2.5 h, and then well
contents were harvested with distilled water (5 washes/well) into a
final volume of 1 mL. Microscopic examination of harvested wells showed
that well contents were completely removed. Harvested material was
plated at 0.1 mL per 90-mm-diameter SDA petri plate. Inoculated SDA
plates were incubated for 24 h at 35°C and then at room
temperature for 24 h, resulting in formation of discrete colonies
for counting. Percent killing [reduction of inoculum colony forming
units (CFUs)] was calculated using the formula [1 -
(experimental CFUs/inoculum CFUs)] x 100.
Antifungal assay
Longer-term assays allowed assessment of effector cell activity
in fungal inhibition. A 48-h assay was used to determine inhibition of
conidia germination and or hyphal growth by BAMs from the different
groups of treated mice. The colorimeteric XTT + coenzyme Q system
was used to measure the quantitative metabolic reduction of XTT by
viable fungal cells [16
, 17
]. The
quantitative change of the yellow substrate solution to the soluble
orange metabolized, reduced form of XTT was measured by absorbance at
405 nM using a microplate reader (Dynex Technologies Inc., Chantilly,
VA). Previous work established the linear relationship between the
number of germinated conidia with subsequent hyphal growth and degree
of XTT metabolism [16
, 18
].
Spleen cells
Spleens were removed from mice and weighed, and single cell
suspensions were prepared. Spleen cells were counted with a
hemocytometer, and the total number of spleen cells per spleen was
calculated.
Statistics
Statistically significant differences between groups were
determined by the Student’s t-test with significance set at
P < 0.05. When several groups were compared with a
single control group, Bonferroni’s adjustment to the t-test
was used.
|
RESULTS
|
|---|
Effect of GM-CSF on DEX suppression of BAM conidiacidal activity
BAMs from DEX-treated mice had significantly (P<0.01)
decreased conidiacidal activity [15±5%, n (number of
experiments]=6) compared with that of control BAMs (35±3%), BAMs
from GM-CSF-treated mice (38±5%), or BAMs from GM-CSF +
DEX-treated mice (39±1%) (Fig. 1
). A typical experiment is detailed in Table 1
. When BAMs were omitted from the assay, conidial CFUs were
insignificantly different from those in the time-zero inoculum. The
conidiacidal activity of control BAMs and the effect of DEX treatment
were not altered when the ex vivo studies were performed with a
fivefold increase in effector/target ratio (n=1). These
results clearly demonstrated the in vivo suppression of BAM
conidiacidal activity by DEX and the blocking of this effect by GM-CSF.
The specificity of the GM-CSF effect was demonstrated by concurrent
study with G-CSF, which also failed to affect BAM conidiacidal activity
when given alone but failed to alter the effect of DEX when both were
given simultaneously in vivo (n=2).
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Figure 1. Effect of in vivo treatments on BAM killing of A. fumigatus
conidia. Bars represent mean percents ± SD of conidia
killed by BAMs from saline-, GM-CSF-, DEX-, or GM-CSF +
DEX-treated mice.
|
|
Effect of GM-CSF on DEX suppression of BAM antihyphal activity
The effect of DEX ± GM-CSF on the antifungal activity of BAM
was also measured using the XTT assay. The extent of conidia
germination and subsequent hyphal growth in cocultures was determined
by this method. Figure 2
shows that growth was significantly inhibited [65%;
(P<0.01)] by control BAMs and BAMs from mice treated with
GM-CSF + DEX (55%, P<0.05) compared with growth in
cultures without BAMs. Although BAMs from DEX-treated mice inhibited
growth by 29%, this difference was not significant
(P>0.05) compared with growth without BAMs. Inhibition of
BAMs by DEX (29%) was significantly (P<0.05) less than
inhibition by control BAMs (65%) or BAMs (55%) from GM-CSF +
DEX-treated mice (Fig. 2)
.
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Figure 2. Inhibition of conidia germination and hyphal growth by BAMs. Shown are
differences in mean absorbance (Delta Absorbance) ±
SD for four determinations of metabolized XTT by hyphae
derived from 48-h cocultures of BAMs and conidia.
|
|
Effect of treatments on spleen weight and cellularity
DEX treatment significantly (P<0.01; four experiments,
each with five mice per group) decreased spleen weight to half normal
(mean spleen weights±SD: saline-treated mice, 0.135±0.015
g; DEX-treated mice, 0.07±0.015 g). This effect was not blocked by
simultaneous treatment with GM-CSF (0.075±0.01 g). Similarly, the
cellularity (number of spleen cells recovered per spleen) of spleens
from DEX-treated mice was significantly (P<0.01) reduced by
more than fivefold compared with normal cellularity (Fig. 3
). Concomitant treatment with GM-CSF and DEX did not reverse the
effect of DEX on spleen cellularity (Fig. 3)
.
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Figure 3. Effect of treatments on spleen cellularity. Bars indicate mean numbers
of recovered spleen cells ± SD from five spleens in
each treatment group. Results are representative of four experiments,
as described in the text.
|
|
Effect of treating mice with GM-CSF and then DEX
GM-CSF was given i.p. to mice, and 24 h later DEX was
administered. BAMs collected 24 h after the GM-CSF + DEX
treatments killed 29 ± 1% of conidia (P<0.01)
(Fig. 4
). On the other hand, BAMs from mice treated first with saline and
then DEX had significantly (P<0.01) decreased conidiacidal
activity (8±4%). BAMs from mice given GM-CSF first and then saline
killed 24 ± 4% of conidia (Fig. 4)
.
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Figure 4. Effect of GM-CSF first and then DEX on BAM killing of A.
fumigatus conidia. Bars represent mean percent killing ±
SD by BAMs in two experiments. The horizontal axis
indicates sequential treatments of the mice from which BAMs were then
derived.
|
|
Spleens from mice given GM-CSF first and then DEX had significantly
(P<0.01) decreased size and weight compared with spleens
from mice given GM-CSF first and then saline (Fig. 5
). This indicates that GM-CSF could not abrogate the effect of DEX
in this compartment.
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Figure 5. Effect of GM-CSF first and then DEX or saline on spleen weight. Bars
represent the mean weights ± SD of spleens (five per
group) from mice treated with GM-CSF first and then saline (GM/Sal) or
DEX (GM/Dex) or from mice treated with saline first and then DEX (Dex).
gm, grams.
|
|
Effect of treatment with DEX first and then GM-CSF on BAM
conidiacidal activity
In another experiment, BAMs from mice treated with saline first
and then GM-CSF killed 27% (P<0.01) of conidia. By
contrast, BAMs from mice given DEX first and then GM-CSF killed 11% of
conidia, which was not significant (P>0.05) activity and
which was similar to the 7% killing by BAMs from mice given DEX and
then saline. This indicates that GM-CSF given later could not reverse
the effect of DEX on BAMs.
Spleens from mice (four mice per group) treated with DEX and then
GM-CSF (0.081±0.009 g) or saline (0.074±0.009 g) weighed
significantly less that spleens from mice given saline and then GM-CSF
(0.117±0.029 g). These and the above data (Fig. 5)
show that the
effect of DEX on spleen size and weight can not be reversed by GM-CSF
given either before or after DEX exposure.
|
DISCUSSION
|
|---|
The percent killing of A. fumigatus conidia by human
[19
] or murine [20
] BAMs reported by
others is similar to the level reported here of killing by BAMs from
saline-treated mice. On the other hand, we are not aware of published
reports about the effect of DEX in vivo on BAM conidiacidal activity ex
vivo. The same can be said for the effects of GM-CSF or GM-CSF +
DEX in vivo on ex vivo killing of conidia by murine BAMs.
The dose of DEX used in vivo here for suppression (0.8 mg/mouse, 23
mg/kg of body weight) was within the range of doses used in studies by
others who investigated in vivo effects of DEX on interferon (IFN)-
production by spleen cells [21
] or nitric oxide
production by peritoneal macrophages [22
]. Our regimen
consisted of a single dose of DEX i.p. followed by testing 24 h
later. By comparison, one group [21
] administered DEX
(0.02, 0.1, or 0.75 mg/kg) orally for 7 days prior to assays, and
another group [22
] treated mice with DEX (0.3, 3, 10, or
30 mg/kg) subcutaneously for 3, 6, or 16 days prior to testing
peritoneal macrophages. Clearly our DEX regimen was sufficient to
impair macrophage antifungal activity. Whether different doses,
regimens, and routes of DEX administration would change our results
remains under investigation.
We used a second method to measure the antifungal activity of BAMs from
treated mice; namely, the XTT assay. This method measured the sum of
events, i.e., inhibition of conidia germination, killing of conidia,
and outgrowth of viable conidia taking place in cocultures of BAMs from
the different groups of treated mice.
These ex vivo results reflected what could take place in the
bronchoalveolar compartment of lungs after exposure to conidia. In this
respect, Waldorf et al. [23
] reported a significant
difference in killing of conidia ingested in vivo by BAMs from control
mice (70%) versus BAMs from cortisone acetate-treated mice (39%)
assayed ex vivo.
Use of GM-CSF in AIDS patients [24
], bone marrow
transplantation patients [25
], and myelocytic leukemia
patients [26
] has been reported. The multiple doses used
in these clinical situations (1.9 µg/kg/day) were much smaller that
the single dose use here (14.2 µg/kg) but not as large as multiple
doses (50 µg/kg daily for 3 days) used in a study with rats
[27
]. Additional studies are necessary to find the
optimal dose of GM-CSF to block DEX suppression of BAMs as reported
here.
Although G-CSF would not be expected to affect macrophages directly,
G-CSF in vivo has secondary effects that can profoundly affect cellular
immunity [28
]. GM-CSF but not G-CSF (at the same
milligrams-per-kilogram dose) blocked the suppression of BAM by DEX.
This result suggests some degree of GM-CSF specificity in blocking DEX
suppression of BAMs for conidiacidal activity. We speculate that GM-CSF
acts directly on BAMs, which have receptors for GM-CSF, thus blocking
the suppression of BAMs by DEX. GM-CSF studies on BAMs have shown that
GM-CSF regulates BAM proliferation, morphology, and differentiation
[29
].
G-CSF in vitro has been shown to block DEX suppression of human
neutrophil antifungal activity for hyphae of A. fumigatus
[30
]. The effect of GM-CSF was not investigated in that
study. Because neutrophils have receptors for GM-CSF and GM-CSF
enhances neutrophil antifungal activity against A. fumigatus
[18
], it might be possible to block DEX suppression of
both BAM and neutrophils by GM-CSF.
We confirmed that DEX decreases spleen weight and cellularity, as has
been reported by others [22
]. In our study, GM-CSF did
not prevent this effect of DEX on spleen weight or cellularity. This
observation is important because it suggests that DEX used for
depressing lymphocyte-mediated immunity would still be effective
despite GM-CSF use, under circumstances in which GM-CSF could restore
some relevant antimicrobial activity otherwise accompanying DEX
immunosuppression. Tsutsui and Kamiyama [21
] have
reported that although DEX decreases spleen cellularity severalfold,
the percentages of CD3+, CD4+,
CD8+, and B220+ cells do not change. It remains
to be determined whether concomitant DEX and GM-CSF treatment results
in changes in percentages of lymphocyte phenotypes.
We investigated the effect of sequential treatments, e.g., GM-CSF first
and then DEX or vice versa, on BAM conidiacidal activity. The results
were similar to those of sequential studies done in vitro
[11
]; namely, GM-CSF given first blocked DEX given
later, but GM-CSF did not block DEX when DEX was given first. These
results support previous observations that prior signaling (IFN-
activation of macrophages) protects macrophages from immunosuppression
by hydrocortisone acetate [31
]. Additional insights into
the mechanism of the interactions we describe here, with respect to the
effects on cytokine networks, are currently being sought.
In summary, protection in the pulmonary compartment against DEX
suppression by GM-CSF but not in other systemic compartments has
potential for improving the design of therapeutic protocols for
patients at risk of pulmonary aspergillosis.
Received January 17, 2001;
revised July 23, 2001;
accepted August 1, 2001.
|
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G. Quezada, N. V. Koshkina, P. Zweidler-McKay, Z. Zhou, D. P. Kontoyiannis, and E. S. Kleinerman
Intranasal Granulocyte-Macrophage Colony-Stimulating Factor Reduces the Aspergillus Burden in an Immunosuppressed Murine Model of Pulmonary Aspergillosis
Antimicrob. Agents Chemother.,
February 1, 2008;
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[Abstract]
[Full Text]
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J. Xu, R. Lucas, M. Schuchmann, S. Kuhnle, T. Meergans, A. P. Barreiros, A. W. Lohse, G. Otto, and A. Wendel
GM-CSF Restores Innate, But Not Adaptive, Immune Responses in Glucocorticoid-Immunosuppressed Human Blood In Vitro
J. Immunol.,
July 15, 2003;
171(2):
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[Abstract]
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ABSTRACT
INTRODUCTION
