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and Tumor Necrosis Factor-
Determine Resistance to Paracoccidioides brasiliensis Infection in Mice
From the Departments of Immunology*
and
Pathology,
Faculty of Medicine of
Ribeirão Preto, University of São Paulo, São Paulo,
Brazil; the Departments of Pathology,
University of Brasília and Catholic University of Brasília,
Brasília, Brazil; and The Institute of Medical Microbiology,
Immunology and Hygiene,§
Technical University
of Munich, Munich, Germany
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(IFN-) and tumor
necrosis factor-
(TNF-) in the resistance to
Paracoccidioides brasiliensis (Pb) infection,
mice with homologous disruption of the IFN- (GKO) or TNF-
receptor p55 (p55KO) were infected with the parasite. GKO and
p55KO, but not wild-type (WT) mice, were unable to
control the growth of yeast cells and the mice succumbed to infection
by days 16 and 90 after infection, respectively. Typical
inflammatory granulomas were found only in WT mice. In
contrast, knockout mice presented an inflammatory infiltrate
composed of a few neutrophils, mononuclear,
epithelioid, and multinuclear giant cells forming incipient
granulomas in GKO mice and without granuloma formation in p55KO mice.
Besides, both groups of knockout mice exhibited elevated
numbers of yeast forms in agreement with colony-forming unit counts in
organs. Compared with WT, splenocytes from infected GKO mice
cultured with the Pb F1 fraction produced lower TNF- levels,
whereas leukocytes from infected p55KO mice produced similar amounts of
TNF- but higher levels of IFN-. Moreover, splenocytes
from infected WT mice produced higher levels of nitric oxide (NO)
resulting in a lower T-cell proliferative response to Con A than
uninfected WT, or infected p55KO and GKO mice. On the
contrary, the addition of IFN- to splenocytes from infected
GKO mice resulted in higher NO production and lower T cell
proliferation. Taken together, these findings suggests that
endogenous TNF-, acting through the p55 receptor,
and IFN- mediate resistance to Pb infection and induce NO production
that determines marked T cell unresponsiveness.
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In the acute form of clinically manifest infection, there is an involvement of the reticuloendothelial system, a nonspecific hypergammaglobulinemia, a depressed cellular immune response, a diffuse inflammatory granulomatous response, and concomitant fungus dissemination. The chronic form presents a broad spectrum of clinical manifestations with frequent damage of the lung and oropharyngeal mucosa and a profound impairment of the immune response.3 In this phase of infection, an epithelioid inflammatory granulomatous reaction is known to prevent the dissemination of the fungus.4
Athymic mice do not control dissemination of the fungus, suggesting
that cell-mediated immunity is an important host defense mechanism
against Pb infection.5,6
However, there is a T cell
dysfunction in patients and infected mice that may be related to
alterations in the ratio of T cell subpopulations, suppressive effects
of fungal components, and an imbalance in the levels of cytokine
production.7-10
The cellular immune response against
fungal antigens that occurs in resistant mice results in macrophage
activation and granuloma formation.11
Tumor necrosis
factor- (TNF-) produced by macrophages in response to the Pb cell
wall component11
is required for macrophage accumulation
and differentiation into epithelioid cells, and for persistence of
well-formed granulomas.12
Interferon- (IFN-) can
activate infected macrophages to secret TNF- and to inhibit the
replication of Pb.13
Recently, experiments
performed on Pb-infected mice treated with anti-IFN- revealed an
exacerbation of pulmonary infection and earlier fungal
dissemination.14
In the present study we evaluated the role of IFN- and TNF-
in the resistance to Pb infection in mice. Using mice genetically
deficient in IFN- (GKO) or TNF- receptor p55 (p55KO), we
could demonstrate that both cytokines are involved in the resistance to
Pb infection, granuloma formation, and control of fungus
dissemination. In addition, our data suggest that IFN- and
TNF- modulate the production of cytokines and nitric oxide (NO) and
the T-cell proliferative response in Pb-infected mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Breeding pairs of mice with targeted disruption of the IFN-
(GKO mice)15
and TNF- receptor p55 (p55KO)
genes16
were obtained from Jackson Laboratories (Bar
Harbor, ME) and Amgen Institute (Toronto, Canada), respectively.
Breeding stock backcrossed on C57Bl/6 were obtained and the genotype of
p55KO and GKO mice determined by polymerase chain reaction of DNA as
previously described.16,17
Male C57Bl/6 wild-type (WT),
GKO, and p55KO mice, 6 to 8 weeks old, were bred and maintained in
microisolator cages in the animal housing facility of the Department of
Immunology, University of São Paulo, Ribeirão Preto,
Brazil.
Parasite and Mice Infection
Yeast cells of virulent Pb 18 strains were cultured at 37°C in Fava-Netto’s medium18 for 7 to 14 days. The yeast cells were harvested and washed three times in phosphate-buffered saline (PBS), pH 7.2. Viability of yeast cells was determined as previously described.19 The animals were infected intravenously with 1 x 106 viable yeast cells in 100 µl of PBS.
Assay for Organ Colony-Forming Units
The dissemination of fungus in lungs, livers, and spleens was assayed as previously described.20 The organs were removed, weighed, homogenized in sterile PBS, pH 7.2, and serially diluted. Aliquots of 100 µl were dispensed into Petri dishes, in duplicates, containing brain-heart infusion agar (Difco Laboratories, Detroit, MI) supplemented with 4% (v/v) of normal horse serum and 5% (v/v) of Pb 192 broth yeast culture filtrate from 2-week-old cultures as source of growth-promoting factor.21 Plates were incubated at 37°C, and colonies were counted 7 to 14 days later. Results were expressed as numbers of colony-forming units (CFU) ± SE per gram of tissue.
Preparation and Fractionation of Pb18 Cell Walls
Fungus cell walls were obtained as previously described.11 Briefly, yeast forms were sonicated and lipids from the cell walls were removed by treatment with chloroform/methanol (2:1, v/v) with stirring at room temperature for 2 hours. Extracts were separated by centrifugation at 500 x g for 5 minutes. The resulting insoluble cell residue was named the cell wall fraction. The cell wall was further treated with 1 N NaOH and gently stirred at room temperature for 1 hour. The alkali-insoluble sediment was washed with water until it reached pH 7.0 and then washed with ethanol, followed by acetone and diethyl ether. The resulting white powder was named F1 fraction and contained <0.05 ng/ml of bacterial endotoxin, as determined by the Limulus amebocyte assay (Sigma Chemical Co., St. Louis, MO).
Proliferation Assay and Nitrite Quantification
Spleen cells from uninfected (day zero) or Pb-infected mice were washed in Hanks’ medium and incubated for 4 minutes with lysis buffer (one part of 0.17 mol/L Tris and nine parts of 0.16 mol/L ammonium chloride). The cells were washed and suspended to a concentration of 5 x 106 cells per ml in RPMI 1640 (Flow Laboratories, McLean, VA) supplemented with 5% fetal calf serum (Life Technologies Inc., Bethesda, MD), 5 x 10-2 mol/L 2-ß-mercaptoethanol, 2 mmol/L L-glutamine, and antibiotics (all from Sigma). The cells were cultured in flat-bottom 96-well plates (Corning Glass Works, Corning, NY) at 1 x 106/well with or without Con A (2 µg/ml) for 72 hours at 37°C in a humidified 5% CO2 incubator. To assess proliferation, 0.5 µCi/well of [3H]TdR (Amersham Corp., Arlington Heights, IL) was added during the final 18 hours of culture, the cells were harvested and radioactivity was measured in a scintillation counter. In some experiments, to inhibit the inducible nitric oxide synthase (iNOS), we added 200 µmol/L of NG-methyl-L-arginine (LNMMA, Sigma). Data were expressed as means (±SE) of counts per minute of triplicate cultures.
For nitrite quantification, splenocytes (2 x
106
cells/ml) from WT, GKO, and p55KO animals
were cultured in triplicate for 48 hours in medium alone or medium
containing Con A (2 µg/ml) in the presence or absence of 100 U/ml of
IFN-. Duplicates of nitrite concentrations in each culture
supernatant were assayed in a microplate by mixing 0.1 ml of culture
supernatant with 0.1 ml of Griess reagent.22
The
A540 was read 10 minutes later, and the nitrite
concentration was determined by reference to a standard curve of 1 to
100 µmol/L NaNO2.
Morphology
Five to seven animals selected at random from each group were sacrificed at 7 and 15 days (GKO) and at 15, 30, and 60 days (p55KO) after infection. The lungs obtained were fixed in 10% formalin for 24 hours and embedded in paraffin. Tissue sections (5 µm) were stained with hematoxylin and eosin (H&E) or impregnated with silver for demonstration of reticulum fibers using standard protocols. WT mice were used as a control.
Cytokine Detection in Culture Supernatants
Spleen cells (2 x 106
cells/ml) from
normal or infected mice were cultured in 24-well tissue culture plates
(Corning) with 2 µg/ml of Con A, 40 µg/ml of Pb18 F1 fraction, or
medium alone for 48 hours at 37°C in a humidified 5%
CO2 incubator. The supernatants were harvested
and stored at -20°C until assayed for IFN-, TNF-,
interleukin (IL)-10, and IL-12, using a two-sandwich enzyme-linked
immunosorbent assay. XMG 1.2 (anti-IFN-), XT22.11 (anti-TNF-),
JES5–2A5 (anti-IL-10), and C17.15.10 (anti-IL-12) were used as capture
monoclonal antibody (mAb). IFN- and TNF- bound to the mAb were
visualized with polyclonal rabbit anti-IFN- or anti-TNF- (both
from Santa Cruz Biotechnology, Santa Cruz, CA), followed by goat
anti-rabbit IgG conjugated with peroxidase (Life Technologies Inc.,
Gaithersburg, MD), whereas IL-10 and IL-12 were detected using
appropriated biotinylated mAbs SXC1 (anti-IL-10) and C15.6
(anti-IL-12), respectively. A standard curve was prepared with specific
cytokines (all from Sigma) and enzyme-linked immunosorbent assay
sensitivities were 0.625 U/ml for IFN-, 312 pg/ml for TNF-, and
390 pg/ml for IL-10 and IL-12.
Statistical Analysis
The results are expressed as the mean ± SE of the indicated number of animals or experiments. Statistical analysis was performed using analysis of variance followed by the parametric Tukey-Kramer test (INSTAT software, GraphPad, San Diego, CA). A P value < 0.05 was considered to indicate statistical significance.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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or the TNF- Receptor p55 Causes Increased
Susceptibility to Pb Infection
To determine the role of IFN- and TNF- in the resistance to
Pb infection, IFN- and TNF- receptor p55 knockout mice were
infected with yeast cells and their survival was compared with that of
littermate controls. We found that whereas 100% of the control
littermate mice survived during the 90-day period of the experiment,
the infected GKO and p55KO mice succumbed by days 16 and 90 after
parasite inoculation, respectively (Figure 1)
. The infected p55KO mice started to
die after day 60 of infection and the mortality rate at day 90 of
infection was 100% when compared with 100% of survival in infected WT
animals. Because infected GKO mice did not survive beyond 16 days, the
fungal loads in these animals were determined on days 4, 7, and 15
postinfection. The results showed a significantly higher amount of
fungus in GKO mice than that verified in infected WT mice
(P < 0.001; Figure 2
, A–C). It is possible that the CFU
numbers at days 7 and 15 are underestimated, because the data represent
the CFU load of mice that have survived. The fungal loads obtained in
the organs from infected p55KO mice (Figure 2
, D–F) also were higher
than those in control-infected WT mice (P <
0.001), except for the spleen at day 15 after infection, for which a
statistically significant difference could not be detected (Figure 2F)
.
Similar fungal loads were also obtained at days 4 and 7 postinfection
in p55KO and WT mice (data not shown).
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and TNF- Control Dissemination of Pb18 Yeast Cells in
the LungHistopathological examination of lung tissue sections revealed marked differences between granulomatous lesions developed in WT mice compared with the lesions observed in both GKO and p55KO after infection with Pb18.
At day 7 postinfection, the WT mice lungs showed a diffuse focal
infiltrate of polymorphs and mononuclear cells in association with few
yeast forms of the fungus. At day 15, diffuse foci of histiocytes,
epithelioid cells, lymphocytes, and a few polymorphs aggregated around
yeast cells, identifiable as epithelioid granulomas, could be seen
(Figure 3A)
. The reticulum fiber staining
clearly demonstrated the early structures of granuloma (Figure 3B)
. At
day 30, well-organized granulomas composed of histiocytes, epithelioid
cells, and multinuclear giant cells aggregated around yeast forms and
surrounded by a rim of lymphocytes and fibroblasts, were formed (Figure 3C)
. The normal pattern of reticulum fibers present in granulomas could
be clearly demonstrated (Figure 3D)
. At day 60 after parasite
inoculation, multiple and confluent typical epithelioid granulomas were
observed (data not shown).
|
. The
reticulum fiber pattern clearly showed the structure of these incipient
granulomas and loss of pulmonary parenchyma architecture (Figure 4B)
.
|
. The reticulum fiber pattern of the
lung parenchyma was preserved (Figure 5B)
. At day 30, the pulmonary
lesions were focal and diffuse, characterized by lymphomononuclear, a
few epithelioid, and multinuclear giant cells in association with
abundant yeast forms, without granuloma formation (Figure 5C)
. The
reticulum fiber pattern of the lung was fairly well preserved (Figure 5D)
. In agreement with CFU counts, the number of yeast forms of the
fungus was markedly increased at both intervals after infection.
Progressively (60 days), the lung parenchyma was severely damaged by a
diffuse mononuclear cell infiltration associated with an increased
number of yeast forms (data not shown).
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Splenocytes from infected WT mice cultured with Con A produced
less IFN- when compared with noninfected mice (day zero corresponds
to baseline, before inoculation; Figure 6A
) and with infected p55KO mice (Figure 6C)
. The TNF- levels in supernatants of cells cultured with Pb F1
fraction increased progressively in infected WT mice on days 7 and 15,
whereas infected GKO mice produced less TNF- during the same period
(Figure 6B)
. On the other hand, splenocytes from infected p55KO and WT
mice cultured with Pb F1 fraction produced similar levels of TNF-
during the course of infection (Figure 6D)
. Cells from infected or
uninfected mice cultured with medium only did not produce detectable
levels of TNF- or IFN-. Although the level of lipopolysaccharide
in the F1 fraction was <0.05 ng/ml, we assayed for TNF- levels in
splenocytes from C3H/HeJ mice that are resistant to lipopolysaccharide.
We found that the levels of TNF- produced by the cells from C3H/HeJ
in the presence of F1 fraction was similar to that found in C57Bl/6
mice (data not shown). Because IL-12 potentiates and IL-10 inhibits the
IFN- production, we assayed for IL-12 and IL-10 in supernatants of
splenocytes cultured with or without F1 fraction and Con A,
respectively. We found that IL-12 levels in the supernatants of
leukocytes from infected WT or knockout mice were similar. For example,
on day 30 after infection, while the IFN- levels were significantly
higher in p55KO than in WT mice (Figure 6C)
, the IL-12 levels were
923 ± 106 and 724 ± 101 pg/ml in infected WT and p55KO
mice, respectively. The levels of IL-10 produced on day 30 after
infection were higher in infected WT mice (913 ± 75 pg/ml) than
in infected p55KO mice (215 ± 30 pg/ml). Increased levels of
IL-10 were also found on day 7 after infection in supernatants of
splenocytes from infected WT mice (5080 ± 540 pg/ml) compared
with GKO mice (1666 ± 28 pg/ml).
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and p55 TNF- Receptor Abrogates Pb-Induced T
Cell Suppression
As previously described,23
splenocytes from WT mice
infected with Pb18 yeast cells proliferated less than cells from normal
mice. Conversely, splenocytes from infected GKO and p55KO mice
exhibited a proliferative response similar to that of noninfected mice
(day zero corresponds to baseline, before inoculation; Figure 7
, A and C). When we made the observation
that NO could be involved in the immunosuppression observed during Pb
infection,23
we compared the NO production by spleen cells
from infected knockout and WT mice. Interestingly, splenocytes from
infected GKO and p55KO mice cultured with Con A produced less NO when
compared with their infected littermates (Figure 7
, B and D).
Considering that abrogation of suppression of Con A-induced proliferate
responses are concomitant to absence of IFN- and decrease in NO
production (Figure 7)
, we evaluated the role of this cytokine in the
control of T cell response and NO production by splenocytes of infected
mice. We thus added IFN- to splenocytes from normal or infected WT
and GKO mice and evaluated the subsequent T-cell proliferative response
and NO production. We found that the addition of IFN- to splenocytes
from infected GKO mice cultured with Con A restored NO production
(Figure 8B)
to the levels detected in
infected WT mice (P < 0.001), and led to a
significant inhibition of Con A-induced T cell proliferation (Figure 8A)
. The addition of IFN- to cell cultures from noninfected GKO mice
led only to a slight increase in the nitrite synthesis (from 0.2
± 0.05 to 1.67 ± 0.49 µmol/L), that was not enough to modify
the cell proliferation. To verify if NO was involved in the mechanism
that mediates inhibition of T cell proliferative responses, we added
the iNOS inhibitor LNNMA to cell cultures. In the absence of Con A, the
addition of LNMMA did not modify the cell proliferation or nitrite
production (data not shown). However, addition of LNMMA to spleen cells
from infected WT mice cultured with Con A abrogated the NO production
and, therefore, reversed the level of T cell proliferation to that
found in cells from infected GKO, as well as uninfected WT and GKO
mice. On the contrary, the addition of LNMMA to cells from normal or
infected GKO mice did not result in alteration in cell proliferation,
thus confirming the role of NO in suppression (Figure 8)
. Therefore,
decreased NO production leads to increased T-cell proliferative
response.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF-
receptor p55 in infected mice was also evaluated. Our results suggest
that IFN- and TNF- are essential for the resistance and survival
of Pb-infected mice. Although the role of IFN- has been extensively
studied in fungal infections such as Candida
albicans18,24,25
and Histoplasma
capsulatum,26,27
the role of this cytokine in
mediating resistance or susceptibility to Pb infection is poorly
understood. In vitro, IFN- plays a pivotal role against
several pathogens,28-30
including Pb yeast
cells,13
through macrophage activation. Treatment of
infected mice with very high amounts of anti-IFN- resulted in
increased fungal burden, although the animals did not die until 8 weeks
after infection.14
In the present study the infection of
GKO mice resulted in 100% mortality after only 16 days of infection as
a consequence of early fungal dissemination to liver, spleen, and
lungs, whereas WT mice were resistant to infection. Histological
examination of lungs from infected GKO mice confirmed the yeast cells
were widespread throughout the major organs. These data suggest that
mice lacking a functional IFN- gene were unable to contain and
control a virulent Pb infection, besides the intense inflammatory
reaction and formation of incipient granulomas associated with a great
number of yeast cells. Moreover, our data could also show that TNF-,
acting through the p55 receptor, is also important to control parasite
dissemination, parasite growth, and the inflammatory response.
Infection of p55KO mice, whose only abnormality is a lack of p55
receptor,16
resulted in increased fungal burden and
absence of granuloma formation. In fact, the granulomatous inflammatory
reaction, a specialized and efficient tissue response against certain
parasites,31
requires TNF-, which is supposed to be
responsible for attracting and activating effector cells, as well as
for macrophage accumulation and differentiation into epithelioid
cells.32
Our results agree with recent studies showing
that TNF- activities mediated by the p55 receptor are important in
granuloma formation in response to bacteria16,33
and
protozoa.34
Accordingly, we could not detect typical
granuloma formation in either GKO or p55KO, suggesting that both
TNF-, signaling via the p55 receptor, and IFN- are involved in
the mediation of granuloma formation in response to Pb. The lesions
observed in the lungs of infected p55KO mice showed a small number of
apparently typical epithelioid cells, in accordance with observations
in p55KO mice inoculated with live Calmette-Guérin
bacillus.35
The survival of infected p55KO mice was longer in comparison with
infected GKO mice probably because TNF-, acting through the p75
receptor, produces higher amounts of NO than infected GKO mice (Figure 7)
, and, therefore, are more resistant to infection (Figure 1)
, thus
reinforcing the hypothesis that NO controls Pb
infection.23
Similarly, it has been shown that the TNF-
p55 receptor-independent pathway involved TNF- p75 receptor
signaling, because neutralization of TNF- abrogated the ability of
p55KO macrophages to produce sufficient NO to kill Leishmania
major.36
Moreover, the elimination of L.
major was delayed when compared with control animals, suggesting
that this pathway may be less efficient than signaling via the p55
receptor.36
Also, it was observed that mice genetically
deficient in TNF- p55 and p75 receptors succumbed significantly
earlier to the infection with Toxoplasma gondii as compared
with TNF- p55KO mice.34
Taken together, these
observations agree with our hypothesis that in the absence of the
TNF- p55 receptor, part of the function of this receptor is taken
over by the TNF- p75 receptor.
It is well known that IFN- promotes TNF- synthesis by murine
macrophages37
and that IFN- and TNF- act
synergistically to induce antimicrobial activity in many infectious
diseases.38,39
In our model, the greatly reduced capacity
of Pb-infected GKO mice to produce TNF- may be an important factor
in their inability to resist Pb infection, because this cytokine is
important in granuloma formation.12,34
The lungs of GKO
mice showed formation of incipient granulomas probably related to
partial production of TNF-; whereas infected p55KO mice produced
high levels of IFN-, which may help to control parasite growth and
dissemination even in the absence of the TNF p55 receptor, resulting in
higher resistance to infection than that observed in GKO mice. The low
IFN- production by infected WT mice was not due to decreased IL-12
synthesis, because it did not change during the whole infection course.
Also, low levels of IL-10 (data not shown) and high levels of IFN-,
known to inhibit and to activate the iNOS, respectively,29
may contribute to induce NO synthesis and to control fungus
replication.
We have previously shown that mice infected with the protozoan
Trypanosoma cruzi produce high levels of IFN- and
TNF-, which lead to activation of iNOS and NO
production.40,41
Despite its importance as a microbicidal
agent, NO has been shown to be involved in the establishment and
maintenance of lymphocyte unresponsiveness in mice infected with
several parasites,30,40
including fungi.28
Similarly, in Pb infection associated with a classical granuloma
reaction there is a marked suppression of cell proliferative response
to the mitogen Con A (Figure 7)
and IFN-, TNF- (Figure 6)
, and NO
production (Figure 7)
. In the absence of the IFN- and TNF-
receptor p55, however, the proliferative response to Con A was similar
to that verified in cells from normal mice. Interestingly, production
of high levels of NO suppressed the proliferative response to Con A.
This observation was reinforced by the addition of IFN- to
splenocytes from infected GKO mice, which resulted in decreased
proliferative response and increased NO production (Figure 8)
.
Moreover, inhibition of the iNOS by the addition of LNMMA to the
cultures of splenocytes from infected WT mice abrogated NO production
and reverted the proliferative response to values similar to those
found in cells from infected GKO and p55KO mice (Figure 8)
. Indeed, NO
has been associated with a decreased proliferative response to Con A42,43
and a recent report demonstrated that treatment of
Pb-infected mice with a specific inhibitor of NO synthesis prevented
failure of the proliferative capacity of spleen cells in response to
Con A and Pb antigen.23
The low NO production in GKO and
p55KO mice may also contribute to the observed decrease in granuloma
formation, because inhibition of NO metabolism caused a loss of
granulomatous architecture in lesions induced by Calmette-Guérin
bacillus.44
Taken together, these data suggest that NO may
modulate the immune response to Pb antigens in infected mice and may
contribute to the organization of the granulomatous lesion.
In summary, a congenital deficiency in IFN- or the TNF- receptor
p55 results in a pronounced loss of protective immunity in mice
infected with Pb. In association with this impairment of immunity,
generation of NO is compromised, suggesting that IFN- and TNF-
participate in the generation of this mediator that acts as an
immunosuppressor in infections caused by Pb18 and also in controlling
dissemination of the fungus. In accordance with our results, patients
with PCM have been demonstrated to produce lower levels of IFN- and
TNF-, suggesting that these cytokines are important to control the
development of the disease.45
The knowledge of the
regulatory mechanisms that lead to the control of Pb infection in
resistant individuals may contribute to a future immunotherapy for PCM
that affects thousands of people in South and Central America.
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Footnotes |
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Supported by a grant from FAPESP (98/11986–2) and by scholarships from CAPES (J. T. S.), FAPESP (A. F.), and CNPq (J. S. S.; M. A. R.; F. F.).
Accepted for publication February 9, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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for enhanced killing of Paracoccidioides brasiliensis or Blastomyces dermatidis. J Immunol 1988, 140:2786-2789[Abstract]
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C. Arruda, R. C. Valente-Ferreira, A. Pina, S. S. Kashino, R. A. Fazioli, C. A. C. Vaz, M. F. Franco, A. C. Keller, and V. L. G. Calich Dual Role of Interleukin-4 (IL-4) in Pulmonary Paracoccidioidomycosis: Endogenous IL-4 Can Induce Protection or Exacerbation of Disease Depending on the Host Genetic Pattern Infect. Immun., July 1, 2004; 72(7): 3932 - 3940. [Abstract] [Full Text] [PDF]
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A. Pina, R. C. Valente-Ferreira, E. E. W. Molinari-Madlum, C. A. C. Vaz, A. C. Keller, and V. L. G. Calich Absence of Interleukin-4 Determines Less Severe Pulmonary Paracoccidioidomycosis Associated with Impaired Th2 Response Infect. Immun., April 1, 2004; 72(4): 2369 - 2378. [Abstract] [Full Text] [PDF]
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 M.C. Fornazim, A. Balthazar, R. Quagliato Jr, R.L. Mamoni, C. Garcia, and M.H.S.L. Blotta Evaluation of bronchoalveolar cells in pulmonary paracoccidioidomycosis Eur. Respir. J., December 1, 2003; 22(6): 895 - 899. [Abstract] [Full Text] [PDF]
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J. T. Souto, J. C. Aliberti, A. P. Campanelli, M. C. Livonesi, C. M.L. Maffei, B. R. Ferreira, L. R. Travassos, R. Martinez, M. A. Rossi, and J. S. Silva Chemokine Production and Leukocyte Recruitment to the Lungs of Paracoccidioides brasiliensis-Infected Mice Is Modulated by Interferon-{gamma} Am. J. Pathol., August 1, 2003; 163(2): 583 - 590. [Abstract] [Full Text] [PDF]
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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): 938 - 947. [Abstract] [Full Text] [PDF]
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 H.-S. Choi, P. R. Rai, H. W. Chu, C. Cool, and E. D. Chan Analysis of Nitric Oxide Synthase and Nitrotyrosine Expression in Human Pulmonary Tuberculosis Am. J. Respir. Crit. Care Med., July 15, 2002; 166(2): 178 - 186. [Abstract] [Full Text] [PDF]
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A. C. Herring, J. Lee, R. A. McDonald, G. B. Toews, and G. B. Huffnagle Induction of Interleukin-12 and Gamma Interferon Requires Tumor Necrosis Factor Alpha for Protective T1-Cell-Mediated Immunity to Pulmonary Cryptococcus neoformans Infection Infect. Immun., June 1, 2002; 70(6): 2959 - 2964. [Abstract] [Full Text] [PDF]
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F. R. F. Nascimento, V. L. G. Calich, D. Rodriguez, and M. Russo Dual Role for Nitric Oxide in Paracoccidioidomycosis: Essential for Resistance, but Overproduction Associated with Susceptibility J. Immunol., May 1, 2002; 168(9): 4593 - 4600. [Abstract] [Full Text] [PDF]
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