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*
Division of Infectious Diseases, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267; and
Veterans Affairs Hospital, Cincinnati, OH 45220
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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75%) of C57BL/6 mice given mAb to GM-CSF did not survive primary
infection, whereas 88–94% of infected controls survived. Analysis of
leukocytes revealed significantly fewer CD4+ and
CD8+ cells in lungs, but not airways, of
anti-GM-CSF-treated mice as compared with infected controls.
However, the histopathology was similar between the two groups. Lungs
of mice given mAb to GM-CSF manifested depressed levels of TNF-
,
IFN-
, and reactive nitrogen intermediates and elevated levels of
IL-4 and IL-10. Administration of mAb to IL-4, to IL-10, or both
restored protective immunity in GM-CSF-neutralized mice. In secondary
infection, administration of mAb to GM-CSF exacerbated infection but
did not alter survival over 30 days. The character of the inflammatory
response was similar, and no differences were detected in Th1 or Th2
cytokine production between the two groups. Thus, endogenous GM-CSF is
essential for survival in primary but not secondary infection, and
blockade perturbs protective immunity. These findings reveal a new
mechanism whereby GM-CSF contributes to host protection and demonstrate
differences in control of primary and secondary
histoplasmosis. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Host control of infection with Hc requires the production of cytokines
that can directly or indirectly stimulate phagocytes to limit
intracellular growth. The generation of protective immunity to this
microbe is associated with a dominant Th1-type response
(3, 4, 5, 6). Among the endogenous cytokines in mice that
unequivocally contribute to elimination of Hc yeast cells from host
tissues are IL-12, IFN-, and TNF- (3, 4, 5, 6, 7, 8, 9, 10). In
primary infection, neutralization of any one of these three during the
acute stages of infection impairs host defenses, and mice succumb to
i.v. or intranasal (i.n.) challenges with yeast cells (3, 4, 5, 7, 8, 9, 10). In secondary infection, IFN- and TNF- are
requisite for survival of mice given yeasts i.n., but the former is
dispensable in animals injected i.v. (9, 10).
The pleiotropic cytokine, GM-CSF, expresses a number of beneficial
effects on host defenses. Among its many biological activities, it can
enhance hemopoiesis of myeloid lineage cells, thereby causing an influx
into the circulation and into inflamed tissues (11, 12).
GM-CSF also promotes the microbicidal and tumoricidal capacity of
macrophages (M
) and increases their class II MHC expression
(13, 14, 15). One previous publication had reported that
recombinant GM-CSF stimulated human monocyte-derived M to express
fungistatic activity against Hc, although the mechanism by which it
exerts a propitious effect in vitro has not been identified
(16). This finding raises the intriguing possibility that
GM-CSF may be important in the protective immune response to this
fungus. Nevertheless, virtually nothing is known regarding the
influence of endogenous GM-CSF to host defenses in either primary or
secondary histoplasmosis. To determine its contribution, we have
analyzed the effect of mAb to GM-CSF on the protective immune response
to pulmonary histoplasmosis using an established murine model induced
by i.n. injection of yeast cells.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male C57BL/6 mice, 6 wk old, were purchased from The Jackson Laboratory (Bar Harbor, ME). Athymic nude mice, 6 wk old, were purchased from the National Cancer Institute (Frederick, MD) and used to produce ascites. All animal experiments were done in accordance with the Animal Welfare Act guidelines of the National Institutes of Health.
Preparation of Hc and infection of mice
Hc yeasts (strain G217B) were prepared as described (5). This strain is a prototypical virulent strain of this fungus (5). To produce infection in naive mice, animals were infected i.n. with 2.5 x 106 Hc yeasts in a 50 µl volume. For secondary histoplasmosis, mice were initially inoculated with 104 yeasts i.n. in a volume of 50 µl. Six to 8 wk later, previously exposed animals were rechallenged i.n. with 2.5 x 106 yeasts.
Organ culture for Hc
Recovery of Hc was performed as described (17). Fungal burden was expressed as mean CFU per whole organ ± SEM. The limit of detection is 102 CFU.
Abs
Ascites-derived rat anti-mouse GM-CSF mAb and rat anti-mouse IL-10 mAb were produced from the hybridoma MP1-22E9 (rat IgG2a) and JES 2A5 (rat IgG2b), respectively. The cell lines were obtained from Dr. J. Abrams (DNAX Research Institute, Palo Alto, CA). The concentration of rat IgG in ascites was assessed by ELISA and calculated by linear regression from a rat IgG (Organon Teknika, Durham, NC) standard curve. Rat anti-mouse IL-4 mAb (11B.11, rat IgG1) was obtained from the Biological Response Modifiers Program (National Cancer Institute). All Abs contained <5 pg/ml of endotoxin as determined by Limulus amebocyte lysate test (BioWhittaker, Walkersville, MD).
Treatment of mice with neutralizing mAb to GM-CSF, IL-10, and IL-4
Mice were injected i.p. with 500 µg of mAb to GM-CSF 24 h before challenge with Hc and an equal amount 24 h postinfection. This dose was selected based on preliminary experiments demonstrating that the lungs of Hc-infected mice administered mAb to GM-CSF contained <20 pg/ml of this cytokine. Mice were given 500 µg of mAb each week thereafter. In studies with anti-IL-4 and anti-IL-10 mAb, mice received 2 mg and 1 mg, respectively, on day 0 of infection and were given 1 mg each week. Control animals received an equal amount of rat IgG concomitantly.
Cytokine measurement
Lungs from infected mice (n = 5–6) were removed
on days 3, 5, 7, and 14 of primary infection or days 7, 14, and 21 of
secondary infection. Tissue was homogenized in 10 ml of RPMI 1640,
centrifuged at 1500 x g, filter sterilized, and stored at
-70°C until assayed. The protein concentration of homogenates ranged
from 2.7 to 5.7 mg/ml. There were no significant differences
(p > 0.05) in protein content between
GM-CSF-neutralized mice and those given rat IgG at each time point
assayed. Commercially available ELISA kits were used to measure
IFN-, IL-4, IL-10, and TNF- (Endogen, Cambridge, MA). IL-12 was
assayed by sandwich ELISA (PharMingen, San Diego, CA) specific for
mouse IL-12 p70 protein. The sensitivity was >100 pg/ml.
Histology
Lungs were removed and tissues were fixed in 10% formalin and embedded in paraffin blocks. Sections (5 µm) were stained with hematoxylin and eosin or with silver (Grocott) for fungal elements. Analysis of the sections was performed in a "blinded" fashion.
Bronchoalveolar lavage (BAL) and single-cell suspension from lungs
BAL was performed on day 7 of primary and days 14 and 21 of secondary infection to obtain inflammatory cells. The trachea was exposed and intubated using a 1.7-mm OD polyethylene catheter. Cells were harvested by instilling PBS free of Ca2+ and Mg2+ in 1-ml aliquots. Approximately 5 ml of lavage fluid were retrieved per mouse. To isolate mononuclear cells from lungs, mice were sacrificed and lungs flushed with 20 ml of HBSS by inserting a catheter into the right heart. The lungs were excised and teased apart with forceps and homogenized by sequential passage through 16-, 18-, and 20-gauge needles. Mononuclear cells were isolated by separation on a 40–70% Percoll (Pharmacia, Piscataway, NJ) gradient (6).
FACS analysis
BAL and lung cells were adjusted to 5 x
105/200 µl in HBSS containing 10% FBS and
0.02% sodium azide and stained with 0.5 µg of one of the following
FITC-labeled mAbs (PharMingen): anti-CD4 (clone RM4-5),
anti-CD8 (clone 53-6.7), anti-Ly-6G (Gr-1), (clone RB6–8C5,
which recognizes polymorphonuclear cells),
anti-I-Ab (clone 25-9-17), Mac-3 (clone
M3/84, detects tissue M), or isotype-matched rat IgG mAb. The
samples were washed and fixed in 2% paraformaldehyde until analyzed on
a flow cytometer.
Reactive nitrogen intermediates (RNI) assay
BAL cells from rat IgG-treated and mAb to
anti-GM-CSF-treated mice (n = 5/group) were
obtained on days 3, 5, and 7 of primary and secondary infection. After
washing twice, cells were plated at 1.5 x 105
cells per well in 48-well plates in DMEM supplemented with 10% FBS.
Nonadherent cells were removed after 2 h and monolayers were
stimulated with LPS (Sigma, St. Louis, MO) (1 µg/ml) plus IFN-
(100 ng/ml) or IFN- (100 ng/ml) plus TNF- (100 ng/ml).
Supernatants were collected 48 h after seeding, and nitrite was
measured using Cayman’s nitrate/nitrite assay kit (Alexis, San Diego,
CA). Data are presented as micromolars of NO2
.
Statistics
Student’s t test was used to compare groups if the data achieved normality, otherwise the Wilcoxon rank sum test was used. Survival data was analyzed using the log rank test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mice inoculated i.n. with Hc were treated with mAb to GM-CSF or
rat IgG and observed over a 30-day period. The former began to appear
ill on days 10–11 postinfection. They were noted to have decreased
mobility, ruffled fur, and huddling. These symptoms progressed over the
next several days until animals became moribund. In two experiments,
survival was strikingly altered by blockade of endogenous GM-CSF as
compared with infected controls (p < 0.0001)
(Fig. 1
).
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). Lungs of GM-CSF-neutralized mice
contained 1.1 log10 more CFU
(p < 0.001) than control lungs, but the burden
of Hc in spleens was similar (p > 0.05). In a
second experiment, the difference between the mAb to GM-CSF-treated
mice and controls in recovery of Hc at day 7 of infection was 
0.5
log10 (p < 0.05); the
number of Hc CFU in spleens was similar between the two groups. In this
second experiment, we sacrificed mice at day 14 of infection and
analyzed the number of Hc CFU in lungs and spleens. The CFU in lungs of
recipients of mAb to GM-CSF were 2.5 log10 higher
than in infected controls (p < 0.001), whereas
the quantity of Hc CFU in spleens did not differ significantly between
groups (p > 0.05). Thus, neutralization of
endogenous GM-CSF was associated with impaired clearance of Hc and
failure to control the infectious process.
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In a separate set of studies, the course of secondary infection in mice
administered mAb to GM-CSF was examined. Mice were inoculated with
104 yeasts and 6–8 wk later were injected with
mAb to GM-CSF or rat IgG and rechallenged with 2.5 x
106 yeasts. All mice survived a 30-day
observation period (data not shown). The fungal burden in the lungs of
GM-CSF-neutralized mice was similar to that of infected controls on day
7 (p > 0.05), but exceeded that of controls on
days 14 (p < 0.01) and 21
(p < 0.05) (Fig. 3). In spleens, the only significant
difference was found on day 14 of experiment 1 in which organs from
infected controls contained far less Hc yeasts
(p < 0.01) than mAb to GM-CSF recipients (Fig. 3). Thus, neutralization of endogenous GM-CSF in secondary infection
blunted the clearance of Hc yeasts, especially in the lungs, but did
not lead to uncontrolled growth of the organism.
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We sought to determine whether administration of mAb to GM-CSF was
associated with perturbations in the production of other cytokines
known to be influential in primary and/or secondary infection. IFN-,
TNF-, IL-4, IL-10, and IL-12 were analyzed because they augment
(IFN-, TNF-, and IL-12) or impair (IL-4 and IL-10) host defenses
to this fungus (3, 4, 5, 6, 7, 8, 9, 10). Mice were treated with mAb to
GM-CSF or rat IgG and infected with 2.5 x 106
yeasts; at days 3, 5, 7, and 14 postinfection, cytokine levels were
measured in lung homogenates. When compared with controls, the levels
of TNF- in lungs of treated animals was significantly less than
controls at days 3 and 5 of infection (p <
0.01), but was higher than controls on days 7 and 14 postinfection
(Fig. 4). IFN- levels in
GM-CSF-neutralized mice were similar on day 3, but exceedingly less
than controls on days 5 and 7 (p < 0.01, day
5; and p < 0.04, day 7) (Fig. 4). By day 14, they were
similar between the groups. The quantity of IL-12 was comparable
between controls and mAb to GM-CSF recipients, except on day 7 in which
IL-12 was higher (p < 0.01) in
GM-CSF-neutralized mice. IL-4 levels in lungs of these animals exceeded
controls (p < 0.01) on days 5, 7, and 14, and
IL-10 levels were greater than controls on days 7 and 14
(p < 0.05, day 7; and p <
0.01, day 14).
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and TNF- levels did not
differ (p > 0.05) between the two groups. IL-4
and IL-10 were similar on days 7 and 21, but significantly lower
(p < 0.009) in mAb to GM-CSF recipients on day
14 (Fig. 4
). Histopathological examination of lung parenchyma
Lung tissue of infected controls and mice given mAb to GM-CSF was examined at days 7 and 14 after primary infection to determine whether there were differences in the inflammatory response to Hc in these respective groups. At day 7, mild to moderate perivascular lymphoid cuffing was observed in lung parenchyma of infected controls. An admixture of neutrophils and granulomatous inflammation was present involving between 30 and 90% of the lung tissue. In anti-GM-CSF-treated animals, the inflammatory response was quite similar. There was mild perivascular lymphoid cuffing and a pyogranulomatous response that involved 20–80% of lung parenchyma. At day 14, the inflammatory response in infected controls had shifted to a strictly granulomatous reaction that affected between 40 and 90% of the lung tissue. In addition, diffuse lymphocytic infiltration of tissue was present. In mice infected for 14 days and treated with mAb to GM-CSF, the tissue reaction remained pyogranulomatous and occluded between 20 and 40% of the pulmonary parenchyma. No lymphocytic infiltration was observed (data not shown).
Lung tissue from rechallenged mice was examined on days 7, 14, and 21 postinfection. In infected controls, there was severe peribronchial and perivascular infiltration of an equal number of lymphocytes and mononuclear phagocytes on day 7. Neutrophils were sparse and scattered throughout the inflamed tissue. The histological picture was similar at this time in GM-CSF-neutralized mice. On days 14 and 21, there was a range of inflammation in both groups extending from mild infiltration of lymphocytes and mononuclear phagocytes to massive infiltration of these cells in the perivascular and peribronchial areas. The extent and severity of inflammation did not differ between the two groups (data not shown).
FACS analysis of infiltrating cells in lungs and lavage fluid
Histopathological examination reveals the architecture of
inflammation, but does not provide information concerning the precise
composition of cells involved in this process. Therefore, we determined
if administration of mAb to GM-CSF altered the numbers of cells in
lungs and lavage fluid in primary infection. The proportion of
CD4+ and CD8+ cells, M
(Mac-3+), neutrophils
(Gr-1+), and I-A+ cells was
determined by FACS, and the absolute numbers calculated. These cell
populations were selected because of their know influence on host
defenses to Hc (10, 18, 19). The number of
CD4+ and CD8+ cells was
significantly less (p = 0.03) in lungs of mAb
to GM-CSF recipients than in infected controls (Table I). Numbers of M, neutrophils, and
I-A+ cells did not differ
(p > 0.05) between the two groups.
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).
We also analyzed the phenotype of cells in lungs and BAL from mice
rechallenged with Hc. Mice infected for 14 and 21 days were examined
because those time periods were associated with alterations in CFU. As
shown in Table II, no differences in the
numbers of CD4+, CD8+,
Gr-1+, Mac-3+, and
I-A+ cells were detected in either lung
parenchyma or BAL.
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RNI production in primary infection
NO is an important mediator of host resistance to primary, but not
secondary, Hc infection (9, 10). Therefore, we examined
RNI production by alveolar M from infected controls and mice given
mAb to GM-CSF. Groups of mice were treated with rat IgG or with mAb to
GM-CSF and at 3, 5, and 7 days postinfection, and alveolar M were
harvested, stimulated with LPS plus IFN- or TNF- plus IFN-,
and assayed for NO2. Alveolar M from mice
administered rat IgG released elevated quantities of RNI
(p < 0.01) in response to LPS plus IFN- at
days 3, 5, and 7 as compared with unstimulated cells (Fig. 5). In contrast, the release of RNI by
cells exposed to LPS and IFN- in mice treated with mAb to GM-CSF did
not differ significantly (p > 0.05) from that
of unstimulated controls on days 3 and 5 postinfection. By day 7, RNI
production by alveolar M incubated with LPS plus IFN- was greater
than that (p < 0.05) of unstimulated cells
(Fig. 5). Similar results were obtained when TNF- plus IFN- was
used as a stimulus (data not shown).
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Because the levels of IL-4 and IL-10 were raised compared with
controls during the course of primary infection, we determined if the
elevated levels contributed to the impairment in the protective immune
response. Groups of mice received mAb to GM-CSF and either rat IgG, mAb
to IL-4, mAb to IL-10, or both and were evaluated for burden of
infection at 1 wk and survival over 30 days. Hc CFU in lungs of
GM-CSF-neutralized mice given mAb to IL-4, IL-10, or IL-4 plus IL-10
was significantly less (p 
0.04) than those
given mAb to GM-CSF alone (Fig. 6A). Fungal recovery in lungs
of GM-CSF-neutralized mice administered mAb to IL-4, IL-10, or both was
similar to that of the infected controls (p >
0.05). In spleens, mice given both mAb to GM-CSF and IL-4 contained
less CFU (p < 0.03) than recipients of mAb to
GM-CSF alone or infected controls (Fig. 6B).
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C). All mice in the groups given either mAb
to IL-4 or to IL-10 or both survived. At 30 days, all the surviving
mice were sacrificed, and the quantity of Hc CFU was assessed in lungs
and spleens. The organs from all the groups contained
<103 CFU. Thus, survival was associated with
clearance of the fungus. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Because GM-CSF is pivotal in generation of myeloid lineage cells
(11, 12), a likely explanation for the observed effects of
mAb to GM-CSF on protective immunity was that blockade reduced
recruitment of phagocytes. This assumption was not supported by the
data. In either primary or secondary infection, the numbers of
neutrophils and M in lungs and lavage fluid were similar or
increased in mice given mAb to GM-CSF as compared with controls.
Furthermore, the organization of the inflammatory response, as
manifested by histopathology, was not altered by administration of mAb
to GM-CSF.
Although ingress of phagocytes was not decreased, the number of
CD4+ and CD8+ cells in
lungs was sharply lower in GM-CSF-neutralized mice as compared with
controls during primary infection. In Hc infection,
CD4+ cells are the major generators of IFN-,
and this cytokine is necessary for survival in primary histoplasmosis
(17, 18). A reduction in CD4+ cells
can account, in part, for the diminished IFN- production in lungs of
mice given mAb to GM-CSF. CD8+ cells also
contribute to protective immunity but in an IFN--independent manner
(17). The decrease in both populations likely contributed
to weakened host defenses. Because alteration in numbers of T cells was
detected only in lung, the influence of endogenous GM-CSF on the influx
of inflammatory cells in infected parenchyma differs from that of
airways.
Neutralization of GM-CSF was accompanied by aberrant cytokine
generation in the lung. Levels of either TNF- or IFN- or both
were reduced during the early stages of infection (7 days), but
returned to control levels by days 7 and 14, respectively. Endogenous
IFN- and TNF- are unequivocally necessary for controlling primary
infection and both must be present during the acute phase of infection
in order that the host eliminate Hc (3, 4, 9, 10, 17).
Decreases in the levels of these two cytokines following neutralization
of GM-CSF contributed to the exacerbation of infection. Although the
low levels of IFN- could be attributed partially to fewer
CD4+ and CD8+ cells, it was
not associated with depressed amounts of IL-12, which is pivotal for
generation of IFN- in Hc infection (3, 4).
Impaired generation of RNI by alveolar M incubated with either of
two potent stimuli, IFN- plus LPS or with TNF- plus IFN-, was
detected in mice given mAb to GM-CSF. The failure to release RNI during
the acute phase most likely added to the progressive nature of the
infection because NO is required for resolution of primary, but not
secondary, disease (10). Either alone or in concert,
TNF- and IFN- are important stimuli for release of RNI
(20). In Hc infection, neutralization of TNF- is
associated with poor RNI generation and progressive infection
(9). Impaired RNI production in GM-CSF-neutralized animals
can be a result of the diminished levels of IFN- and/or TNF-.
However, GM-CSF also can independently stimulate the production of NO
(21, 22). Thus, neutralization of GM-CSF in conjunction
with decreases in TNF- and IFN- account for the blunted release
of RNI.
A possible explanation for the unrestrained growth of Hc in mice given
mAb to GM-CSF is diminished generation of oxygen intermediates. GM-CSF,
TNF-, and IFN- induce an oxidative burst by phagocytes (12, 23, 24, 25). Neutralization of endogenous GM-CSF combined with
depressed production of TNF- and IFN- would blunt release of
oxygen intermediates. This explanation is unlikely because Hc yeasts
can replicate in the presence of a vigorous oxidative burst, and in
murine M, yeasts inhibit the respiratory burst (26, 27).
The lungs of mice given mAb to GM-CSF manifested markedly elevated IL-4 and IL-10 levels, two cytokines that exacerbate histoplasmosis (4, 9). Administration of mAb to IL-4 or to IL-10 to GM-CSF-neutralized mice resulted in a reduction of fungal burden in lungs at 1 wk and markedly improved survival. Thus, IL-4 and IL-10 independently exert an inimical effect on the course of infection in mice given mAb to GM-CSF.
One consideration for the perturbations in cytokine production in lungs
of mice given mAb to GM-CSF is the increased burden of Hc. This
contention is not supported by previous data in which large fungal
burdens of Hc-infected animals are not consistently associated with
modulation of IFN-, TNF-, IL-4, or IL-10 levels in lungs
(3, 9). Furthermore, on days 14 and 21 of secondary
infection, the increased fungal burden of mice given mAb to GM-CSF was
not accompanied by alterations in any of the four cytokines referenced
above. Thus, no direct relationship exists between fungal burden and
cytokine levels in the lungs.
GM-CSF is known to interact with IFN- and TNF-. In
GM-CSF-knockout mice exposed to LPS, levels of circulating IFN- are
less than that of controls, but TNF- levels were similar
(28). In this model system, there is a GM-CSF-IFN-
axis, but not an interaction between GM-CSF and TNF-. Alternatively,
exogenous GM-CSF enhances TNF- transcription and TNF- induces
GM-CSF synthesis (29, 30). In experimental primary Hc
infection, there exists a link between endogenous GM-CSF production and
IFN- and TNF- generation.
The findings also document a connection between endogenous GM-CSF and
IL-4 and IL-10 in primary infection. Others have reported that IL-4 and
IL-10 can inhibit monocyte production of GM-CSF in vitro
(31), but there is virtually no information regarding the
ability of GM-CSF to regulate IL-4 or IL-10 generation. The elevated
IL-4 and IL-10 levels at days 5 and 7 may have been caused by a
decrease in IFN-, but this possibility is unlikely because
IFN--deficient mice that were infected with Hc did not manifest
absolute increases in IL-4 levels (3, 5).
Mice congenitally deficient in GM-CSF by homologous recombination might complement the studies performed with mAb neutralization (32). These mice accumulate abundant amounts of surfactant lipids and protein in the alveolar spaces by an early age and develop a disease that mimics alveolar proteinosis. This condition can alter normal lung physiology and air exchange. Accordingly, the preexisting lung pathology and compromised lung function in these mice presents a barrier to their use for Hc infection.
In secondary infection, treatment with mAb to GM-CSF only delayed
clearance of the fungus, but did not alter survival of mice. The
impaired clearance was not associated with marked disturbances in
IFN-, TNF-, IL-4, or IL-10 generation. No differences in either
the histopathology or the cellular composition of inflammation were
detected between controls and mAb to GM-CSF recipients. Neutralization
of GM-CSF in secondary infection does not produce the striking
perturbations in immunity as observed in primary histoplasmosis. Hence,
compensatory mechanisms must exist to control secondary infection.
In summary, endogenous GM-CSF is important in the formation of the protective immune response to Hc. These data indicate that there are complex networks involved in Hc infection and that blockade of GM-CSF in primary infection produces a plethora of perturbations of the immunity that culminate in the death of the animal. The findings do establish that GM-CSF production is closely intertwined in the signaling events that lead to up-regulation of Th1 and dampening of Th2 cytokines. Furthermore, the results highlight differences in the contribution of endogenous GM-CSF to primary and secondary infection.
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Footnotes |
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2 Address correspondence and reprint requests to: Dr. George S. Deepe, Jr., Division of Infectious Diseases, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45267. E-mail address:
3 Abbreviations used in this paper: Hc, Histoplasma capsulatum; BAL, bronchoalveolar lavage; i.n., intranasal; M, macrophage; RNI, reactive nitrogen intermediates.
Received for publication April 20, 1999. Accepted for publication August 16, 1999.
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G. S. Deepe Jr. and R. S. Gibbons Protective and Memory Immunity to Histoplasma capsulatum in the Absence of IL-10 J. Immunol., November 15, 2003; 171(10): 5353 - 5362. [Abstract] [Full Text] [PDF]
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L. A. Gildea, R. Gibbons, F. D. Finkelman, and G. S. Deepe Jr. Overexpression of Interleukin-4 in Lungs of Mice Impairs Elimination of Histoplasma capsulatum Infect. Immun., July 1, 2003; 71(7): 3787 - 3793. [Abstract] [Full Text] [PDF]
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G. S. Deepe, Jr., and R. S. Gibbons Cellular and Molecular Regulation of Vaccination with Heat Shock Protein 60 from Histoplasma capsulatum Infect. Immun., July 1, 2002; 70(7): 3759 - 3767. [Abstract] [Full Text] [PDF]
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G. S. Deepe Jr. and R. Gibbons V{beta}6+ T Cells Are Obligatory for Vaccine-Induced Immunity to Histoplasma capsulatum J. Immunol., August 15, 2001; 167(4): 2219 - 2226. [Abstract] [Full Text] [PDF]
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G. S. Deepe Jr. and R. Gibbons Protective Efficacy of H Antigen from Histoplasma capsulatum in a Murine Model of Pulmonary Histoplasmosis Infect. Immun., May 1, 2001; 69(5): 3128 - 3134. [Abstract] [Full Text] [PDF]
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L. A. Gildea, R. E. Morris, and S. L. Newman Histoplasma capsulatum Yeasts Are Phagocytosed Via Very Late Antigen-5, Killed, and Processed for Antigen Presentation by Human Dendritic Cells J. Immunol., January 15, 2001; 166(2): 1049 - 1056. [Abstract] [Full Text] [PDF]
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 G. S. Deepe Jr. and R. Gibbons Recombinant Murine Granulocyte-Macrophage Colony-Stimulating Factor Modulates the Course of Pulmonary Histoplasmosis in Immunocompetent and Immunodeficient Mice Antimicrob. Agents Chemother., December 1, 2000; 44(12): 3328 - 3336. [Abstract] [Full Text]
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R. Allendoerfer and G. S. Deepe Jr. Regulation of Infection with Histoplasma capsulatum by TNFR1 and -2 J. Immunol., September 1, 2000; 165(5): 2657 - 2664. [Abstract] [Full Text] [PDF]
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