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*
Centenary Institute of Cancer Medicine and Cell Biology, Newtown, Australia;
Department of Medicine, University of Sydney, Sydney New South Wales, Australia; and
Department of Veterinary Anatomy and Pathology, University of Sydney, Sydney, New South Wales, Australia
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(LT) may act at various stages of the
host response to Mycobacterium tuberculosis. To dissect
the effects of TNF independent of LT, we have used C57BL/6 mice with
a disruption of the TNF gene alone (TNF-/-). Twenty-one
days following aerosol M. tuberculosis infection there
was a marked increase in the number of organisms in the lungs of
TNF-/- mice, and by 28–35 days all animals had
succumbed, with widespread dissemination of M.
tuberculosis. In comparison with the localized granulomas
containing activated macrophages and T cells in lungs and livers of
C57BL/6 wild-type (wt) mice, cellular infiltrates in
TNF-/- mice were poorly formed, with extensive regions of
necrosis and neutrophilic infiltration of the alveoli. Phenotypic
analysis of lung homogenates demonstrated similar numbers of
CD4+ and CD8+ T cells in TNF-/-
and wt mice, but in TNF-deficient mice the lymphocytes were restricted
to perivascular and peribronchial areas rather than colocated with
macrophages in granulomas. T cells from TNF-/- mice
retained proliferative and cytokine responses to purified protein
derivative, and delayed-type hypersensitivity to purified protein
derivative was demonstrable. Macrophages within the lungs of
TNF-/- and wt mice showed similar levels of MHC class II
and inducible nitric oxide synthase expression, and levels of serum
nitrite were comparable. Thus, the enhanced susceptibility of
TNF-/- is not compensated for by the presence of LT,
and the critical role of TNF is not in the activation of T cells and
macrophages but in the local organization of
granulomas. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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and TNF for
the stimulation of macrophage intracellular killing through the
induction of high levels of reactive nitrogen intermediates
(RNI)5, 8 . The major source
of TNF is mononuclear phagocytes, although T cells, particularly after
appropriate stimulation, are capable of producing substantial amounts
of TNF 9 . As a highly potent proinflammatory cytokine, TNF has
broad-ranging activities from the up-regulation of adhesion molecules
on endothelium to the induction of apoptosis. TNF release correlates
with antimycobacterial mechanisms in the murine model 10 , as the peak
of production coincides with a decrease in the bacillary load.
Pretreatment of murine macrophages cultured in vitro with TNF and
IFN- induces significant bactericidal activity, with a 100-fold
reduction in the survival of intracellular mycobacteria 11 . TNF is
required for this mycobacteriostatic effect, as treatment of
mycobacterium-infected macrophage cultures with anti-TNF antiserum
or soluble anti-TNFRI abrogated the inhibition of mycobacterial
growth and the release of RNI 8, 12, 13 .
The in vivo role of TNF in protective responses to mycobacterial
infection has been assessed using neutralization with anti-TNF
antiserum and mice deficient in the TNFRI 4, 14 . Both approaches
resulted in the decreased development of granulomas, failure to
restrict mycobacterial growth, and decreased survival. These
experiments implicated a role for TNF in the control of mycobacterial
infection, but the relative contributions of TNF and the related
cytokine lymphotoxin- (LT) to protection are uncertain. There is
30% amino acid identity between TNF and LT, which is secreted in
a trimeric form as LT3 15 . Both TNF and LT, however, bind TNFRI
with similar affinities 16 , so experiments in TNFRI-deficient mice
fail to distinguish between the roles of TNF and LT. Moreover, the
effects observed with the polyclonal anti-TNF antisera may have
been due to neutralization of either TNF or LT. To define the
contribution of TNF to the course of M. tuberculosis
infection we have used mice in which the TNF gene has been disrupted
directly in the C57BL/6 mouse strain 17 and that retain normal
expression of LT 18 . This avoided the problems associated with
using F1 hybrids of the 129 strain mice or the requirement
for extensive backcrossing. Using a model of low dose M.
tuberculosis aerosol infection, which mimics the major route of
infection in humans, we demonstrate that TNF itself is crucial for the
development of protective immunity against mycobacteria. Although there
was evidence of the Ag-specific T cell activation and activation of
macrophages, the growth of mycobacteria was unrestrained, leading to
the death of TNF-/- mice. Activated T cells
were present in the lungs of TNF-/- mice in
similar proportions as in wild-type (wt) mice, but the failure of these
T cells to form well-defined granulomas in TNF-deficient animals
indicates that TNF is essential for the cellular recruitment and
organization underlying this process.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Control wt mice were 6- to 8-wk-old C57BL/6 strain mice obtained from Animal Resources Center (Perth, Australia). TNF gene knockout mice prepared on the C57BL/6 background have been previously described 17 . All mice were housed under specific pathogen-free conditions at the Centenary Institute animal facility until infection with M. tuberculosis, when they were transferred and maintained in a level 3 physical containment facility.
Aerosol infection of mice with tuberculosis
A Middlebrook airborne infection apparatus (Glas-Col, Terre Haute IN) was used to infect mice with M. tuberculosis H37Rv (ATCC no. 27294, American Type Culture Collection, Manassas, VA) strain that had been grown from a low passage seed lot in Proskauer-Beck liquid medium to midlog phase, aliquoted, and frozen at -70°C. The mice were placed in the exposure chamber of the apparatus, and a 106/ml suspension of the bacteria was placed into the nebulizer. This concentration delivered 100 bacilli into the lungs of exposed mice. The numbers of viable bacteria in target organs were followed over time by plating serial dilutions of whole organ homogenates on supplemented Middlebrook 7H11 nutrient agar (Difco, Detroit, MI) and counting bacterial colony formation after incubation for 20 days at 37°C. The data are expressed as the log10 value of the mean number of bacteria recovered per organ (n = 4 animals).
Lung preparations
Animals were sacrificed by carbon dioxide narcosis at appropriate time points. The lung vascular bed was cannulated and perfused with a warm solution containing PBS, 0.02% BSA (Sigma, St. Louis, MO), and 20 U/ml heparin (Fisons Pharmaceuticals, Sydney, Australia). One lung was homogenized, and a 100-µl aliquot was used for serial dilutions from 10-1-10-8 and spread in duplicate quadrants of bacterial plates. The other lung was chopped into small pieces using scissors and incubated in RPMI 1640 (Sigma) containing optimal concentrations of collagenase (Sigma) and DNase (Sigma) for 60 min at 37°C. At the end of this incubation period, any large particulate debris were removed from the suspension by passage through sterile 100-µm pore size mesh, and cells were collected by centrifugation (480 x g at 4°C for 5 min).
Phenotypic analysis of pulmonary infiltrates
The following mAb were used: CD4 (CT-CD4; Caltag, South San
Francisco, CA), CD8 (CT-CD8; Caltag), CD16/32 (2.4G2; PharMingen, La
Jolla, CA), CD44 (IM 7.8.1; Sigma), CD45RB (16A; Sigma), Ly-6G
(RB6-8C5; PharMingen) for flow cytometry. Staining of cells was
performed in a 96-well round-bottom plate (Becton Dickinson, Lincoln
Park, NJ) with 2 x 105 cells/well. Cells were
pelleted by centrifugation (480 x g at 4°C for 1
min), the supernatant was aspirated, and Fc receptors were blocked by
labeling with CD16/32 (for 15 min at 4°C). The cells were washed by
centrifugation (2% BSA and 0.1% NaN3 in PBS, 480 x
g at 4°C for 1 min), and diluted Ab combinations were
added (for 15 min at 4°C). Following washing, the samples were fixed
overnight in 10% neutral buffered formalin (Fronine, Riverstone,
Australia) and analyzed on the FACScan (Becton Dickinson, San Jose,
CA).
T cell responses to mycobacterial Ags
Mediastinal lymph node cells were harvested from wt and
TNF-/-, and a single cell suspension was
prepared by sieving through 200-µm pore size mesh and resuspending
the cells in culture medium (RPMI 1640; Sigma), 10% FCS (CSL
Bioscience, Melbourne, Australia), 2 mM L-glutamine (Flow
Laboratories, Sydney, Australia), 50 mM 2-ME (Sigma) buffered with 10
mM HEPES (Sigma), and 10 mM sodium bicarbonate (BDH, Melbourne,
Australia)). Cell suspensions were plated at 2 x 105
cells/well in 96-well plates and incubated for 72 h at 37°C in
5% CO2. The cells were stimulated with medium alone,
purified protein derivative (PPD) of M. tuberculosis
(Statens Seruminstitut, Copenhagen, Denmark), or PMA (Sigma). The
proliferation of lymphocytes was determined using the Alamar Blue assay
(Astral Scientific, Gymea, Australia). Briefly, for the last 16 h
of a 72-h culture, Alamar Blue dye was added to a concentration of 10%
(v/v), and Alamar Blue fluorescence (oxidation-reduction) was measured
by absorbance at 540 nm (reduced form) and 620 nm (oxidized form) using
a Titertek Multiscan Mcc/340 plate reader (ICN Pharmaceuticals, Costa
Mesa, CA). The concentrations of IFN- in culture supernatants were
determined by ELISA using an mAb capture assay with Abs R4-6A2 and
XMG1.2-biotin (Endogen, Woburn, MA) following the manufacturer’s
instructions. Avidin-alkaline phosphatase (Sigma) and
n-nitro-phenyl-phosphate (1 mg/ml in 10 mM
NaHCO3 and 0.1 mM MgCO3 (pH 6.3)) were used as
the colorimetric reagents, and absorbance was measured at 405 nm.
Serum nitrite measurements
Serum nitrite was assayed by a modification of the nitrate kit for food analysis (Boehringer Mannheim, Mannheim, Germany). Briefly, serum nitrate was reduced to nitrite using nitrate reductase. Nitrite levels were determined using the Greiss reagent 19 (3% phosphoric acid, 1% p-aminobenzene-sulfonamide, and 1% n-1-napthylethylenediamide (Sigma)); 100 µl of this was added to 30 µl of reduced sera. Samples were incubated for 5 min at room temperature, and absorbance was read at 540 nm.
Determination of delayed-type hypersensitivity (DTH) response to PPD
Infected mice were challenged in one footpad with 10 µg of PPD in 50 µl of PBS and in the other with PBS alone. The swelling in each footpad was measured at 24 h using callipers (Mitutoyo 97227-10; Extech, Boronia, Australia), and the Ag-specific DTH response was determined as the difference in swelling between PBS-injected footpad against PPD-injected footpads. The PPD preparation did not induce swelling in the footpads of uninfected animals.
Histological and immunohistochemical analyses
Lung and liver tissue samples were fixed in 10% neutral buffered formalin, set in paraffin blocks, and sectioned at 5 µm. Sections were stained with hematoxylin and eosin or the Ziehl-Neelsen (ZN) stain for acid fast bacilli. Slides were examined blind and analyzed using 37 criteria for differences in cellular infiltrate. Granulomas were defined as collections of 10 or more macrophages and T lymphocytes within the peripheral lung or liver. The average number of granulomas in liver sections was determined for five random high power fields (x400). The expression of MHC class II and iNOS within tissues was investigated with indirect immunofluorescence labeling. Air-dried frozen sections (4–6 µm) were double stained with rabbit anti-mouse iNOS polyclonal Ab (Upstate Biotechnology, Lake Placid, NY) and rat anti-mouse Ia mAb (P7/7), followed by F(ab')2 of affinity-purified goat anti-rat Ig conjugated to FITC (Caltag) in combination with TRITC-conjugated goat anti-rabbit IgG (Southern Biotechnology Associates, Birmingham, AL). Ab incubations were conducted for 20 min in a moist chamber at room temperature, and after each incubation the sections were washed three times for 5 min each time with PBS. The distribution of lymphocytes was demonstrated by immunoperoxidase staining of deparaffinized sections with biotinylated rat anti-Thy1.2 (30H12) and streptavidin-conjugated horseradish peroxidase (Sigma) followed by color development with Sigma Fast diaminobenzidinex. Sections were examined on a Leica Leitz DMRBE (Deerfield, IL).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is crucial for the control of aerosol M.
tuberculosis infection
TNF-/- and wt mice were infected with
virulent M. tuberculosis, and their clinical condition and
the growth of bacteria were followed over time.
TNF-/- mice remained well until day 25, but
then rapidly deteriorated, and all succumbed between days 28 and 35 of
infection (Fig. 1
). By contrast, wt mice
controlled the same infectious dose and survived for >161 days. The
number of mycobacteria recovered from the lungs of
TNF-/- mice increased from day 17, and by day
28 this was 105 times greater than that in wt mice (Fig. 2). There was increased dissemination of
organisms to the liver and spleen of TNF-/-
mice (Fig. 2), and M. tuberculosis was recovered from the
kidneys, bone marrow, and other organs not usually infected in wt mice
(data not shown).
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Both CD4+ and CD8+ T cells are vital to
the resolution of M. tuberculosis infection in the lung.
Therefore, the cell number and phenotype of the responding cells in
TNF-/- mice were assessed. Throughout the
course of the infection, similar numbers of CD4+ and
CD8+ T cells were present in the lungs of both wt control
and TNF-/- mice. At 28 days postinfection,
30% of lung lymphocytes were CD4+, while nearly 20%
were CD8+ (Fig. 3,
a and b). To investigate the activation state of
these cells, CD4+ T cells were stained for the
activation/memory markers CD45RB and CD44 (Fig. 3, c
and d). The CD4+ T cells from both wt and
TNF-/- showed similar levels of
CD44highCD45RBlow expression.
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, e and f), and they were a
significant component of the total leukocyte population by day 28. Differential cellular infiltrate and granulomatous response in the lungs of infected TNF-/- mice
As normal numbers of T cells were detected in lung cellular
homogenates from the TNF-/- mice throughout the
course of the disease, the lungs and livers of
TNF-/- and normal mice were examined
histologically to determine whether the rate of development and the
pattern of cellular responses were different between the
TNF-/- and wt mice. In wt mice a few small
granulomas were present throughout the lungs on day 14, and by day 28
these had grown into several granulomas, 1–1.2 mm in diameter (Fig. 4a), containing intact
macrophages, some lymphocytes, and only occasional neutrophils with no
necrosis (Fig. 4c). In TNF-/- mice
the earliest differences in the lungs were mild to moderate
perivascular and peribronchial accumulations of lymphocytes and plasma
cells evident on days 7 and 14. Consistent with the cytometric
analysis, by day 21 the cellular accumulations in
TNF-/- mice were clearly different, consisting
of groups of alveoli filled with neutrophils and few macrophages and no
lymphocytes. By day 28 these collections were larger in
TNF-/- mice, being 2.2–2.8 mm in diameter
(Fig. 4b). The central regions contained necrotic debris and
fibrin overlying outlines of alveoli with peripheral margins of intact
neutrophils and macrophages. On days 21 and 28 there were prominent
perivascular lymphocytic accumulations and milder peribronchial
infiltrates of mixed mononuclear cells in both control and
TNF-/- mice (Fig. 4, c andd). In areas free of cellular inflammation there was extensive
exudation of proteinaceous fluid into the alveolar lumens of
TNF-/- mice. On ZN staining, the granulomas in
wt mice contain no more than several hundred bacilli per high power
field at 28 days postinfection (Fig. 4e), whereas in
TNF-/- mice the number of bacilli was greatly
increased to about several thousand per high power field (Fig. 4f).
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, g and
h, indicates the colocalization of MHC class II and iNOS
labeling in wt and TNF-/- mice. The iNOS
staining was generally within or around the granulomas in wt mice and
the margins of the necrotic regions in TNF-/-
mice. Increased MHC class II staining was also evident on alveolar
macrophages and the endothelium of blood vessels in other parts of the
lung parenchyma in both groups.
The location of lymphocytes was confirmed with immunoperoxidase
staining. Thy1.2-positive lymphocytes were mixed with macrophages in
the granulomas of normal mice (Fig. 5a). By contrast, in TNF
-/- mice the Thy1.2-positive lymphocytes were
restricted to perivascular and peribronchial regions and were absent
from infiltrates in peripheral lung (Fig. 5, b and
d). The failure of TNF -/- mice to
develop normal granulomas was also evident in the liver, with a
profound reduction in the number of granulomas during the course of
M. tuberculosis infection (Fig. 6). In addition, at 28 days numerous foci
of extramedullary hemopoiesis were present in the livers of
TNF-/-, but not in wt mice.
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The antimicrobial mechanisms of activated mouse macrophages
include the production of RNIs. Therefore, the nitrite levels in the
serum of wt and TNF-/- mice were analyzed
throughout the course of M. tuberculosis infection (Fig. 7). TNF-/- mice
had levels of serum nitrite similar to those in wt mice. This was
consistent with the observed expression of iNOS within pulmonary
macrophages in infected TNF-/- mice (Fig. 4, g and h). Thus, at the time when wt mice begin to
control infection and TNF-/- mice fail to do
so, nitrite and iNOS levels were similar in these mice (Fig. 7).
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release in infected mice are
unaffected by TNF deficiency
To determine the reason for the inability to control mycobacterial
growth, T cell proliferative responses in infected mice were examined.
Fig. 8a demonstrates that in
an in vitro restimulation assay at 3 wk, T cells from the mediastinal
draining lymph nodes of both wt and TNF-/-
infected mice proliferated to the same degree in response to
stimulation with PPD. IFN- is crucial to the protective response to
M. tuberculosis infection. Draining lymph node cells from
infected animals were stimulated with PPD, and IFN- was measured.
Although TNF-/- mice were unable to control
M. tuberculosis infection they were still able to produce
IFN- in an Ag-specific recall response (Fig. 8b).
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It is uncertain which molecules are required for generating a DTH
response to PPD. This was highlighted by the ability of
IFN--deficient mice to mount Ag-specific DTH 20 . To determine
whether TNF-/- mice could also mount this
response, infected mice were challenged in one footpad with 10 µg of
PPD, and the response was compared with that in wt mice. Although
TNF-/- mice could not mount a protective
response in the lungs, they were still able to mount a DTH response to
mycobacterial proteins (Fig. 9).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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mRNA 18 , but LT is unable to compensate for the deficiency of TNF.
The susceptibility to M. tuberculosis correlates with a
paucity in granuloma formation even though there is evidence of both T
cell and macrophage activation. Ag-specific proliferation and IFN-
production by T cells were at levels similar to those in wt animals,
while macrophage activation, as reflected by expression of iNOS and
serum nitrite production, was also comparable in
TNF-/- and wt mice. Earlier studies using
TNFRI-/- mice or neutralizing anti-TNF Ab
suggested a role for TNF in the control of infection with M.
tuberculosis, but these used either very high dose i.v. M.
tuberculosis infection or M. bovis
Calmette-Guérin bacillus infection 4, 14 . In this study low
dose inocula of M. tuberculosis were delivered by the
aerosol route and resulted in disseminated fatal infection, confirming
that TNF is essential for the protective response against tuberculosis.
Moreover, as TNFRI binds both TNF and LT, and polyclonal
anti-TNF Abs may neutralize both cytokines, earlier studies 4, 14
were unable to distinguish between the protective effects of TNF and
LT. Infection of mice with disruption of the TNF molecule alone has
defined the essential contribution of TNF to protective immunity.
TNF may operate at a number of steps in the host response to M.
tuberculosis infection. First, TNF synergizes with IFN- in
vitro for the maximal activation of bactericidal mechanisms in infected
macrophages, including the production of RNI 8, 12 . TNF together with
IFN- was considered necessary for the expression of iNOS by
macrophages 21 , although IFN- can induce low levels of iNOS
activity on its own 22 . Inhibition of TNF with soluble TNFRI in vitro
abrogates NO release and the inhibition of the growth of
Calmette-Guérin bacillus 12 . Intriguingly, the
TNF-/- mice are still able to produce NO (Fig. 7), and iNOS is detectable within their lungs (Fig. 4h).
During M. tuberculosis infection other activating signals
may be sufficient to induce iNOS. This is consistent with the presence
of iNOS mRNA in lungs of M. tuberculosis-infected
TNFRI-deficient mice 14 and immunoreactive iNOS in the brains of
TNF-/- mice with experimental allergic
encephalitis 18, 23 . The inhibition of iNOS function in vivo 24, 25
and the deletion of its gene 26 confirm that RNI are essential for
host resistance to mycobacteria, but RNI synthesis alone is not
sufficient to control mycobacterial infection in
TNF-/- mice. Thus, failure of the activation of
macrophage bactericidal mechanisms alone does not explain the profound
susceptibility of these mice to tuberculosis.
Second, TNF appears crucial for the structural organization of the
cellular response. Despite the presence of activated T cells in the
lungs of TNF-/- in similar numbers and
proportions to those in wt mice, the normal pattern of granuloma
formation is disrupted (Fig. 4b). Previous studies have
demonstrated neutralizing anti-TNF Ab inhibits granuloma formation
in the liver 4, 14 . This is confirmed by the markedly depressed
granulomatous response in the liver of the
TNF-/- mice (Fig. 6). Granuloma formation
requires the activation of Ag-specific T cells, the accumulation of T
cells and monocytes at the site of infection, and their local
organization into a mature granuloma that limits the infection. In
healthy wt mice, this process reduces the bacterial burden, but does
not eliminate infection, so that at 23 wk postinfection mycobacteria
are still demonstrable in the lungs, contained within granulomas (data
not shown). This resembles the situation in humans, in whom
mycobacteria are contained but not eradicated within granulomas in the
lung, leaving the host susceptible to reactivation of tuberculosis upon
immunosuppression. In M. tuberculosis-infected
TNF-/- mice, Ag-specific T cell responses, such
as IFN- production and DTH (Figs. 7 and 8), were comparable to those
in normal mice. Although total lung homogenates contained similar
numbers of CD4+ and CD8+ T cells (Fig. 3), the
lymphocytes accumulated in the perivascular and peribronchial regions
of TNF-/- mice. This is the earliest detectable
histological difference between TNF-/- and wt
mice. Activated CD44highCD45RBlow T cells
appear able to cross the endothelium, but the T cells fail to migrate
from the perivascular region into the inflamed lung, and this
contributes to the deficiency in granuloma formation.
TNF may participate in both the recruitment and migration of T cells into inflamed tissues. This occurs through the TNF-stimulated expression of chemotactic molecules on endothelium and the up-regulation of surface homing molecules on T cells 27, 28 , both of which contribute to the recruitment of Th1 cells into inflamed tissue 29 . However, in the TNF-/- mice there was normal recruitment of T cells into the lung, but failure of movement of the T cells into the infected alveoli to form granulomas. During the evolution of experimental autoimmune encephalitis in the central nervous system of TNF-/- mice, a similar failure of leukocyte migration was observed, with cells accumulating in the perivascular spaces of the brain but not moving normally into the parenchyma 18, 23 .
Recent studies with IL-12-/- mice have
indicated that these mice are unable to generate a DTH response to PPD
during M. tuberculosis infection 30 . By contrast,
IFN--deficient mice can mount a DTH response despite their increased
susceptibility to M. tuberculosis 20 . This suggested that
other soluble factors, such as TNF, may be more important in generating
a DTH response. The preservation of DTH despite the absence of TNF
indicates that this cytokine is not essential for this response. DTH
requires the presence of Ag-reactive T cells and their capacity to
cross endothelium in response to signals and cause dermal edema.
Ag-specific T cells are present in TNF-/- mice,
as evidenced by specific IFN- responses in draining lymph nodes and
the expression of T cell activation markers on lung T cells, but they
are still unable to control the disease. Although the activation and
production of IFN- by T cells are essential for the resolution of
M. tuberculosis infection, clearly this response must occur
within a localized, structurally normal granuloma at the site of
infection for it to be successful.
The movement of mononuclear phagocytes as well as lymphocytes may be
defective in the absence of TNF. Macrophages are normally activated by
TNF to produce a range of locally active chemokines 28 . These
chemokines attract monocytes to the sites of infection and activate
their development into mature macrophages, leading to granuloma
formation, epithelioid cell differentiation and multinucleated giant
cell formation 28 . Other chemokines are induced by TNF. For example,
the release of macrophage inflammatory protein-1 from LPS-stimulated
macrophages is dependent on TNF and IL-1, since coincubation of
LPS-stimulated PBMC with TNF binding protein or IL-1R antagonist
abrogates macrophage inflammatory protein-1 secretion 31 . These
mechanisms contribute to the rapid, transient accumulation of
leukocytes observed following the local injection of TNF 32 .
Reduction in monocyte recruitment also contributes to the failure of
the development of an effective granulomatous response.
Another effect of TNF deficiency is the dysregulation of the
inflammatory response. The increased influx of activated neutrophils in
TNF-/- mice may account for the marked damage
to the lungs during infection. Neutrophil migration and activation
contributes to lung injury in acute respiratory distress syndrome
patients 33 . Neutrophils and their oxidative products cause
endothelial and epithelial cell injury, leading to increased protein
permeability into alveoli and impaired lung function. The combination
of tissue necrosis and the increased protein exudation in areas without
tissue destruction contributes to the death of these mice. This
phenomenon also occurs during M. tuberculosis infection in
other genetically deficient mice, such as IFN- and 
TCR-/- mice 20, 34 . This neutrophil influx
may be an ineffective compensatory response, activated when the correct
T cell/macrophage interaction is disrupted. TNF may play an important
role by influencing local cellular traffic, affecting the positioning
of lymphocytes and monocytes, and limiting the actions of neutrophils
that cause tissue damage rather than protection.
In conclusion, TNF is essential for the control of M.
tuberculosis infection. Its central role appears to be in the
generation of a structurally effective granulomatous response, and this
cannot be compensated for by LT alone. Even though Ag-specific
lymphocytes are activated and cross the vasculature into the lung, they
fail to migrate into the infected tissues and interact with monocytes
to form granulomas and prevent the unrestrained growth of the bacilli.
This effect of TNF deficiency may be mediated by dysregulation of the
chemokine network, which is crucial to the movement of lymphocytes and
monocytes within the lung.
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Footnotes |
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2 These authors contributed equally to this study.
3 Current address: Institut fuer Klinische Mikrobiologie, Hygiene und Immunologie Wasserturmstrasse 3, 91054 Erlangen, Germany.
4 Address correspondence and reprint requests to Dr. W. J. Britton, Centenary Institute of Cancer Medicine and Cell Biology, Locked Bag 6, Newtown, New South Wales 2042, Australia. E-mail address:
5 Abbreviations used in this paper: RNI, reactive nitrogen intermediates; LT, lymphotoxin; wt, wild-type; PPD, purified protein derivative; DTH, delayed-type hypersensitivity; ZN, Ziehl-Neelsen; iNOS, inducible nitric oxide synthase.
Received for publication July 16, 1998. Accepted for publication December 15, 1998.
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References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
restores granulomas and induces parasite egg-laying in schistosome-infected SCID mice. Nature 356:604.[Medline]
stimulated macrophages: regulation by endogenous tumor necrosis factor- and by IL-10. Int. Immunol. 6:693., tumour necrosis factor- and transforming growth factor-ß, during the course of experimental pulmonary tuberculosis. Immunology 90:607.[Medline]
-mediated growth inhibition of Mycobacterium tuberculosis by human alveolar macrophages. J. Immunol. 152:743.[Abstract]
is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 2:561.[Medline]
and TNFß and inhibition of TNF activity. J. Biol. Chem. 266:18324. is mediated by NF-
B proteins. Proc. Natl. Acad. Sci. USA 92:3561. production in lipopolysaccharide-stimulated human adherent blood mononuclear cells is inhibited by the nitric oxide synthase inhibitor N(G)-monomethyl-L-arginine. J. Immunol. 159:5063.[Abstract]
. J. Immunol. 159:3595.[Abstract]
T lymphocytes in acquired immunity to Mycobacterium tuberculosis. J. Immunol. 158:1217.[Abstract]
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S. Bertholet, G. C. Ireton, M. Kahn, J. Guderian, R. Mohamath, N. Stride, E. M. Laughlin, S. L. Baldwin, T. S. Vedvick, R. N. Coler, et al. Identification of Human T Cell Antigens for the Development of Vaccines against Mycobacterium tuberculosis J. Immunol., December 1, 2008; 181(11): 7948 - 7957. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Sadek, F. Y. Yue, E. Y. Lee, G. Gyenes, R. B. Jones, V. Hoffstein, D. G. Munoz, I. Fong, and M. Ostrowski Clinical and Immunologic Features of an Atypical Intracranial Mycobacterium avium Complex (MAC) Infection Compared with Those of Pulmonary MAC Infections Clin. Vaccine Immunol., October 1, 2008; 15(10): 1580 - 1589. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Di Liberto, M. Locati, N. Caccamo, A. Vecchi, S. Meraviglia, A. Salerno, G. Sireci, M. Nebuloni, N. Caceres, P.-J. Cardona, et al. Role of the chemokine decoy receptor D6 in balancing inflammation, immune activation, and antimicrobial resistance in Mycobacterium tuberculosis infection J. Exp. Med., September 1, 2008; 205(9): 2075 - 2084. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Lei, B. L. Plattner, and J. M. Hostetter Live Mycobacterium avium subsp. paratuberculosis and a Killed-Bacterium Vaccine Induce Distinct Subcutaneous Granulomas, with Unique Cellular and Cytokine Profiles Clin. Vaccine Immunol., May 1, 2008; 15(5): 783 - 793. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Rotta, G. Matteoli, E. Mazzini, P. Nuciforo, M. P. Colombo, and M. Rescigno Contrasting roles of SPARC-related granuloma in bacterial containment and in the induction of anti-Salmonella typhimurium immunity J. Exp. Med., March 17, 2008; 205(3): 657 - 667. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Florido and R. Appelberg Characterization of the Deregulated Immune Activation Occurring at Late Stages of Mycobacterial Infection in TNF-Deficient Mice J. Immunol., December 1, 2007; 179(11): 7702 - 7708. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. C. Wong, W. M. Leong, H. K. W. Law, K. F. Ip, J. T. H. Lam, K. Y. Yuen, P. L. Ho, W. S. Tse, X. H. Weng, W. H. Zhang, et al. Molecular Characterization of Clinical Isolates of Mycobacterium tuberculosis and Their Association with Phenotypic Virulence in Human Macrophages Clin. Vaccine Immunol., October 1, 2007; 14(10): 1279 - 1284. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Garlanda, D. Di Liberto, A. Vecchi, M. P. La Manna, C. Buracchi, N. Caccamo, A. Salerno, F. Dieli, and A. Mantovani Damping Excessive Inflammation and Tissue Damage in Mycobacterium tuberculosis Infection by Toll IL-1 Receptor 8/Single Ig IL-1-Related Receptor, a Negative Regulator of IL-1/TLR Signaling J. Immunol., September 1, 2007; 179(5): 3119 - 3125. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. Torrado, S. Adusumilli, A. G. Fraga, P. L. C. Small, A. G. Castro, and J. Pedrosa Mycolactone-Mediated Inhibition of Tumor Necrosis Factor Production by Macrophages Infected with Mycobacterium ulcerans Has Implications for the Control of Infection Infect. Immun., August 1, 2007; 75(8): 3979 - 3988. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. Fremond, D. Togbe, E. Doz, S. Rose, V. Vasseur, I. Maillet, M. Jacobs, B. Ryffel, and V. F. J. Quesniaux IL-1 Receptor-Mediated Signal Is an Essential Component of MyD88-Dependent Innate Response to Mycobacterium tuberculosis Infection J. Immunol., July 15, 2007; 179(2): 1178 - 1189. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. Wu, C. Huang, L. Garcia, A. P. de Leon, J. S. Osornio, M. Bobadilla-del-Valle, L. Ferreira, S. Canizales, P. Small, M. Kato-Maeda, et al. Unique Gene Expression Profiles in Infants Vaccinated with Different Strains of Mycobacterium bovis Bacille Calmette-Guerin Infect. Immun., July 1, 2007; 75(7): 3658 - 3664. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Uchiyama, I. Kawamura, T. Fujimura, M. Kawanishi, K. Tsuchiya, T. Tominaga, T. Kaku, Y. Fukasawa, S. Sakai, T. Nomura, et al. Involvement of Caspase-9 in the Inhibition of Necrosis of RAW 264 Cells Infected with Mycobacterium tuberculosis Infect. Immun., June 1, 2007; 75(6): 2894 - 2902. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Maglione, J. Xu, and J. Chan B Cells Moderate Inflammatory Progression and Enhance Bacterial Containment upon Pulmonary Challenge with Mycobacterium tuberculosis J. Immunol., June 1, 2007; 178(11): 7222 - 7234. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Spohn, R. Guler, P. Johansen, I. Keller, M. Jacobs, M. Beck, F. Rohner, M. Bauer, K. Dietmeier, T. M. Kundig, et al. A Virus-Like Particle-Based Vaccine Selectively Targeting Soluble TNF-{alpha} Protects from Arthritis without Inducing Reactivation of Latent Tuberculosis J. Immunol., June 1, 2007; 178(11): 7450 - 7457. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. M. O'Kane, J. J. Boyle, D. E. Horncastle, P. T. Elkington, and J. S. Friedland Monocyte-Dependent Fibroblast CXCL8 Secretion Occurs in Tuberculosis and Limits Survival of Mycobacteria within Macrophages J. Immunol., March 15, 2007; 178(6): 3767 - 3776. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Basu, S. K. Pathak, A. Banerjee, S. Pathak, A. Bhattacharyya, Z. Yang, S. Talarico, M. Kundu, and J. Basu Execution of Macrophage Apoptosis by PE_PGRS33 of Mycobacterium tuberculosis Is Mediated by Toll-like Receptor 2-dependent Release of Tumor Necrosis Factor-{alpha} J. Biol. Chem., January 12, 2007; 282(2): 1039 - 1050. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. M. Wozniak, A. A. Ryan, and W. J. Britton Interleukin-23 Restores Immunity to Mycobacterium tuberculosis Infection in IL-12p40-Deficient Mice and Is Not Required for the Development of IL-17-Secreting T Cell Responses J. Immunol., December 15, 2006; 177(12): 8684 - 8692. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kurtz, K. P. McKinnon, M. S. Runge, J. P.-Y. Ting, and M. Braunstein The SecA2 Secretion Factor of Mycobacterium tuberculosis Promotes Growth in Macrophages and Inhibits the Host Immune Response Infect. Immun., December 1, 2006; 74(12): 6855 - 6864. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Yimin and M. Kohanawa A Regulatory Effect of the Balance between TNF-{alpha} and IL-6 in the Granulomatous and Inflammatory Response to Rhodococcus aurantiacus Infection in Mice J. Immunol., July 1, 2006; 177(1): 642 - 650. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Tjarnlund, A. Rodriguez, P.-J. Cardona, E. Guirado, J. Ivanyi, M. Singh, M. Troye-Blomberg, and C. Fernandez Polymeric IgR knockout mice are more susceptible to mycobacterial infections in the respiratory tract than wild-type mice Int. Immunol., May 1, 2006; 18(5): 807 - 816. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. Sud, C. Bigbee, J. L. Flynn, and D. E. Kirschner Contribution of CD8+ T Cells to Control of Mycobacterium tuberculosis Infection J. Immunol., April 1, 2006; 176(7): 4296 - 4314. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Ismail, H. L. Stevenson, and D. H. Walker Role of Tumor Necrosis Factor Alpha (TNF-{alpha}) and Interleukin-10 in the Pathogenesis of Severe Murine Monocytotropic Ehrlichiosis: Increased Resistance of TNF Receptor p55- and p75-Deficient Mice to Fatal Ehrlichial Infection Infect. Immun., March 1, 2006; 74(3): 1846 - 1856. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. N. Stewart, H. N. Rivera, R. Karls, F. D. Quinn, J. Roman, and C. A. Rivera-Marrero Increased pathology in lungs of mice after infection with an {alpha}-crystallin mutant of Mycobacterium tuberculosis: changes in cathepsin proteases and certain cytokines Microbiology, January 1, 2006; 152(1): 233 - 244. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Bafica, C. A. Scanga, C. G. Feng, C. Leifer, A. Cheever, and A. Sher TLR9 regulates Th1 responses and cooperates with TLR2 in mediating optimal resistance to Mycobacterium tuberculosis J. Exp. Med., December 19, 2005; 202(12): 1715 - 1724. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Cho and D. N. McMurray Neutralization of Tumor Necrosis Factor Alpha Suppresses Antigen-Specific Type 1 Cytokine Responses and Reverses the Inhibition of Mycobacterial Survival in Cocultures of Immune Guinea Pig T Lymphocytes and Infected Macrophages Infect. Immun., December 1, 2005; 73(12): 8437 - 8441. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S Stenger Immunological control of tuberculosis: role of tumour necrosis factor and more Ann Rheum Dis, November 1, 2005; 64(suppl_4): iv24 - iv28. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Shi, A. Blumenthal, C. M. Hickey, S. Gandotra, D. Levy, and S. Ehrt Expression of Many Immunologically Important Genes in Mycobacterium tuberculosis-Infected Macrophages Is Independent of Both TLR2 and TLR4 but Dependent on IFN-{alpha}{beta} Receptor and STAT1 J. Immunol., September 1, 2005; 175(5): 3318 - 3328. [Abstract] [Full Text] [PDF]
|
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|
|
|
D. R. Roach, H. Briscoe, B. M. Saunders, and W. J. Britton Independent Protective Effects for Tumor Necrosis Factor and Lymphotoxin Alpha in the Host Response to Listeria monocytogenes Infection Infect. Immun., August 1, 2005; 73(8): 4787 - 4792. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. L. Taylor, D. J. Ordway, J. Troudt, M. Gonzalez-Juarrero, R. J. Basaraba, and I. M. Orme Factors Associated with Severe Granulomatous Pneumonia in Mycobacterium tuberculosis-Infected Mice Vaccinated Therapeutically with hsp65 DNA Infect. Immun., August 1, 2005; 73(8): 5189 - 5193. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. P. Simmons, G. E. Thwaites, N. T. H. Quyen, T. T. H. Chau, P. P. Mai, N. T. Dung, K. Stepniewska, N. J. White, T. T. Hien, and J. Farrar The Clinical Benefit of Adjunctive Dexamethasone in Tuberculous Meningitis Is Not Associated with Measurable Attenuation of Peripheral or Local Immune Responses J. Immunol., July 1, 2005; 175(1): 579 - 590. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Guler, M. L. Olleros, D. Vesin, R. Parapanov, and I. Garcia Differential Effects of Total and Partial Neutralization of Tumor Necrosis Factor on Cell-Mediated Immunity to Mycobacterium bovis BCG Infection Infect. Immun., June 1, 2005; 73(6): 3668 - 3676. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Keane TNF-blocking agents and tuberculosis: new drugs illuminate an old topic Rheumatology, June 1, 2005; 44(6): 714 - 720. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
B. M. Saunders, S. Tran, S. Ruuls, J. D. Sedgwick, H. Briscoe, and W. J. Britton Transmembrane TNF Is Sufficient to Initiate Cell Migration and Granuloma Formation and Provide Acute, but Not Long-Term, Control of Mycobacterium tuberculosis Infection J. Immunol., April 15, 2005; 174(8): 4852 - 4859. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Buettner, C. Meinken, M. Bastian, R. Bhat, E. Stossel, G. Faller, G. Cianciolo, J. Ficker, M. Wagner, M. Rollinghoff, et al. Inverse Correlation of Maturity and Antibacterial Activity in Human Dendritic Cells J. Immunol., April 1, 2005; 174(7): 4203 - 4209. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. L. Olleros, R. Guler, D. Vesin, R. Parapanov, G. Marchal, E. Martinez-Soria, N. Corazza, J.-C. Pache, C. Mueller, and I. Garcia Contribution of Transmembrane Tumor Necrosis Factor to Host Defense against Mycobacterium bovis Bacillus Calmette-Guerin and Mycobacterium tuberculosis Infections Am. J. Pathol., April 1, 2005; 166(4): 1109 - 1120. [Abstract] [Full Text] [PDF]
|
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|
|
|
|
V. Rao, N. Fujiwara, S. A. Porcelli, and M. S. Glickman Mycobacterium tuberculosis controls host innate immune activation through cyclopropane modification of a glycolipid effector molecule J. Exp. Med., February 22, 2005; 201(4): 535 - 543. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. E. Pearl, S. A. Khader, A. Solache, L. Gilmartin, N. Ghilardi, F. deSauvage, and A. M. Cooper IL-27 Signaling Compromises Control of Bacterial Growth in Mycobacteria-Infected Mice J. Immunol., December 15, 2004; 173(12): 7490 - 7496. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. T. Giles and J. M. Bathon Serious Infections Associated with Anticytokine Therapies in the Rheumatic Diseases J Intensive Care Med, November 1, 2004; 19(6): 320 - 334. [Abstract] [PDF]
|
|
|
|
 |
|
 M. Florido, M. Borges, H. Yagita, and R. Appelberg Contribution of CD30/CD153 but not of CD27/CD70, CD134/OX40L, or CD137/4-1BBL to the optimal induction of protective immunity to Mycobacterium avium J. Leukoc. Biol., November 1, 2004; 76(5): 1039 - 1046. [Abstract] [Full Text] [PDF]
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|
|
|
|
|
E. J. Kerschen, D. A. Cohen, A. M. Kaplan, and S. C. Straley The Plague Virulence Protein YopM Targets the Innate Immune Response by Causing a Global Depletion of NK Cells Infect. Immun., August 1, 2004; 72(8): 4589 - 4602. [Abstract] [Full Text] [PDF]
|
|
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|
|
|
D. A. Hagge, N. A. Ray, J. L. Krahenbuhl, and L. B. Adams An In Vitro Model for the Lepromatous Leprosy Granuloma: Fate of Mycobacterium leprae from Target Macrophages after Interaction with Normal and Activated Effector Macrophages J. Immunol., June 15, 2004; 172(12): 7771 - 7779. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. M. Wright and J. S. Friedland Regulation of monocyte chemokine and MMP-9 secretion by proinflammatory cytokines in tuberculous osteomyelitis J. Leukoc. Biol., June 1, 2004; 75(6): 1086 - 1092. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. M. S. Algood, P. L. Lin, D. Yankura, A. Jones, J. Chan, and J. L. Flynn TNF Influences Chemokine Expression of Macrophages In Vitro and That of CD11b+ Cells In Vivo during Mycobacterium tuberculosis Infection J. Immunol., June 1, 2004; 172(11): 6846 - 6857. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Honstettre, E. Ghigo, A. Moynault, C. Capo, R. Toman, S. Akira, O. Takeuchi, H. Lepidi, D. Raoult, and J.-L. Mege Lipopolysaccharide from Coxiella burnetii Is Involved in Bacterial Phagocytosis, Filamentous Actin Reorganization, and Inflammatory Responses through Toll-Like Receptor 4 J. Immunol., March 15, 2004; 172(6): 3695 - 3703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. E. Dorman, C. L. Hatem, S. Tyagi, K. Aird, J. Lopez-Molina, M. L. M. Pitt, B. C. Zook, A. M. Dannenberg Jr., W. R. Bishai, and Y. C. Manabe Susceptibility to Tuberculosis: Clues from Studies with Inbred and Outbred New Zealand White Rabbits Infect. Immun., March 1, 2004; 72(3): 1700 - 1705. [Abstract] [Full Text] [PDF]
|
|
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|
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T. W. Wright, G. S. Pryhuber, P. R. Chess, Z. Wang, R. H. Notter, and F. Gigliotti TNF Receptor Signaling Contributes to Chemokine Secretion, Inflammation, and Respiratory Deficits during Pneumocystis Pneumonia J. Immunol., February 15, 2004; 172(4): 2511 - 2521. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Prevot, E. Bourreau, H. Pascalis, R. Pradinaud, A. Tanghe, K. Huygen, and P. Launois Differential Production of Systemic and Intralesional Gamma Interferon and Interleukin-10 in Nodular and Ulcerative Forms of Buruli Disease Infect. Immun., February 1, 2004; 72(2): 958 - 965. [Abstract] [Full Text] [PDF]
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|
|
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M. B. Drennan, D. Nicolle, V. J. F. Quesniaux, M. Jacobs, N. Allie, J. Mpagi, C. Fremond, H. Wagner, C. Kirschning, and B. Ryffel Toll-Like Receptor 2-Deficient Mice Succumb to Mycobacterium tuberculosis Infection Am. J. Pathol., January 1, 2004; 164(1): 49 - 57. [Abstract] [Full Text] [PDF]
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 |
|
 N. Shimono, L. Morici, N. Casali, S. Cantrell, B. Sidders, S. Ehrt, and L. W. Riley Hypervirulent mutant of Mycobacterium tuberculosis resulting from disruption of the mce1 operon PNAS, December 23, 2003; 100(26): 15918 - 15923. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. L. Fuller, J. L. Flynn, and T. A. Reinhart In Situ Study of Abundant Expression of Proinflammatory Chemokines and Cytokines in Pulmonary Granulomas That Develop in Cynomolgus Macaques Experimentally Infected with Mycobacterium tuberculosis Infect. Immun., December 1, 2003; 71(12): 7023 - 7034. [Abstract] [Full Text] [PDF]
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|
|
|
T. M. Lasco, T. Yamamoto, T. Yoshimura, S. S. Allen, L. Cassone, and D. N. McMurray Effect of Mycobacterium bovis BCG Vaccination on Mycobacterium-Specific Cellular Proliferation and Tumor Necrosis Factor Alpha Production from Distinct Guinea Pig Leukocyte Populations Infect. Immun., December 1, 2003; 71(12): 7035 - 7042. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Kaplan, F. A. Post, A. L. Moreira, H. Wainwright, B. N. Kreiswirth, M. Tanverdi, B. Mathema, S. V. Ramaswamy, G. Walther, L. M. Steyn, et al. Mycobacterium tuberculosis Growth at the Cavity Surface: a Microenvironment with Failed Immunity Infect. Immun., December 1, 2003; 71(12): 7099 - 7108. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Kipnis, R. J. Basaraba, J. Turner, and I. M. Orme Increased neutrophil influx but no impairment of protective immunity to tuberculosis in mice lacking the CD44 molecule J. Leukoc. Biol., December 1, 2003; 74(6): 992 - 997. [Abstract] [Full Text]
|
|
|
|
|
|
N. M. Price, R. H. Gilman, J. Uddin, S. Recavarren, and J. S. Friedland Unopposed Matrix Metalloproteinase-9 Expression in Human Tuberculous Granuloma and the Role of TNF-{alpha}-Dependent Monocyte Networks J. Immunol., November 15, 2003; 171(10): 5579 - 5586. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Cowley and K. L. Elkins CD4+ T Cells Mediate IFN-{gamma}-Independent Control of Mycobacterium tuberculosis Infection Both In Vitro and In Vivo J. Immunol., November 1, 2003; 171(9): 4689 - 4699. [Abstract] [Full Text] [PDF]
|
|
|
|
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|
S Ehlers Role of tumour necrosis factor (TNF) in host defence against tuberculosis: implications for immunotherapies targeting TNF Ann Rheum Dis, November 1, 2003; 62(90002): ii37 - 42. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. V. Capuano III, D. A. Croix, S. Pawar, A. Zinovik, A. Myers, P. L. Lin, S. Bissel, C. Fuhrman, E. Klein, and J. L. Flynn Experimental Mycobacterium tuberculosis Infection of Cynomolgus Macaques Closely Resembles the Various Manifestations of Human M. tuberculosis Infection Infect. Immun., October 1, 2003; 71(10): 5831 - 5844. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. M. Aspalter, M. M. Eibl, and H. M. Wolf Regulation of TCR-mediated T cell activation by TNF-RII J. Leukoc. Biol., October 1, 2003; 74(4): 572 - 582. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Botha and B. Ryffel Reactivation of Latent Tuberculosis Infection in TNF-Deficient Mice J. Immunol., September 15, 2003; 171(6): 3110 - 3118. [Abstract] [Full Text] [PDF]
|
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|
|
|
|
W. R. Waters, M. V. Palmer, D. L. Whipple, M. P. Carlson, and B. J. Nonnecke Diagnostic Implications of Antigen-Induced Gamma Interferon, Nitric Oxide, and Tumor Necrosis Factor Alpha Production by Peripheral Blood Mononuclear Cells from Mycobacterium bovis-Infected Cattle Clin. Vaccine Immunol., September 1, 2003; 10(5): 960 - 966. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Sato, J. Schorey, V. A. Ploplis, E. Haalboom, L. Krahule, and F. J. Castellino The Fibrinolytic System in Dissemination and Matrix Protein Deposition During a Mycobacterium Infection Am. J. Pathol., August 1, 2003; 163(2): 517 - 531. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Ehlers, C. Holscher, S. Scheu, C. Tertilt, T. Hehlgans, J. Suwinski, R. Endres, and K. Pfeffer The Lymphotoxin {beta} Receptor Is Critically Involved in Controlling Infections with the Intracellular Pathogens Mycobacterium tuberculosis and Listeria monocytogenes J. Immunol., May 15, 2003; 170(10): 5210 - 5218. [Abstract] [Full Text] [PDF]
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|
|
|
 |
|
 R. Barthel, A. V. Tsytsykova, A. K. Barczak, E. Y. Tsai, C. C. Dascher, M. B. Brenner, and A. E. Goldfeld Regulation of Tumor Necrosis Factor Alpha Gene Expression by Mycobacteria Involves the Assembly of a Unique Enhanceosome Dependent on the Coactivator Proteins CBP/p300 Mol. Cell. Biol., January 15, 2003; 23(2): 526 - 533. [Abstract] [Full Text] [PDF]
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|
|
|
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|
C. A. Murphy, R. M. Hoek, M. T. Wiekowski, S. A. Lira, and J. D. Sedgwick Interactions Between Hemopoietically Derived TNF and Central Nervous System-Resident Glial Chemokines Underlie Initiation of Autoimmune Inflammation in the Brain J. Immunol., December 15, 2002; 169(12): 7054 - 7062. [Abstract] [Full Text] [PDF]
|
|
|
|
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|
H. M. Scott and J. L. Flynn Mycobacterium tuberculosis in Chemokine Receptor 2-Deficient Mice: Influence of Dose on Disease Progression Infect. Immun., November 1, 2002; 70(11): 5946 - 5954. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
D. R. Roach, A. G. D. Bean, C. Demangel, M. P. France, H. Briscoe, and W. J. Britton TNF Regulates Chemokine Induction Essential for Cell Recruitment, Granuloma Formation, and Clearance of Mycobacterial Infection J. Immunol., May 1, 2002; 168(9): 4620 - 4627. [Abstract] [Full Text] [PDF]
|
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|
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|
 R. van Crevel, T. H. M. Ottenhoff, and J. W. M. van der Meer Innate Immunity to Mycobacterium tuberculosis Clin. Microbiol. Rev., April 1, 2002; 15(2): 294 - 309. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Smith, D. Liggitt, E. Jeromsky, X. Tan, S. J. Skerrett, and C. B. Wilson Local Role for Tumor Necrosis Factor Alpha in the Pulmonary Inflammatory Response to Mycobacterium tuberculosis Infection Infect. Immun., April 1, 2002; 70(4): 2082 - 2089. [Abstract] [Full Text] [PDF]
|
|
|
|
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|
M. L. Olleros, R. Guler, N. Corazza, D. Vesin, H.-P. Eugster, G. Marchal, P. Chavarot, C. Mueller, and I. Garcia Transmembrane TNF Induces an Efficient Cell-Mediated Immunity and Resistance to Mycobacterium bovis Bacillus Calmette-Guerin Infection in the Absence of Secreted TNF and Lymphotoxin-{alpha} J. Immunol., April 1, 2002; 168(7): 3394 - 3401. [Abstract] [Full Text] [PDF]
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R. Lang, R. L. Rutschman, D. R. Greaves, and P. J. Murray Autocrine Deactivation of Macrophages in Transgenic Mice Constitutively Overexpressing IL-10 Under Control of the Human CD68 Promoter J. Immunol., April 1, 2002; 168(7): 3402 - 3411. [Abstract] [Full Text] [PDF]
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U. Palendira, A. G. D. Bean, C. G. Feng, and W. J. Britton Lymphocyte Recruitment and Protective Efficacy against Pulmonary Mycobacterial Infection Are Independent of the Route of Prior Mycobacterium bovis BCG Immunization Infect. Immun., March 1, 2002; 70(3): 1410 - 1416. [Abstract] [Full Text] [PDF]
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 W. S. Lim, R.J. Powell, I.D. Johnston, Z. Zhang, H. Correa, R. E. Begue, F. G. De Rosa, S. Bonora, G. Di Perri, A. Myers, et al. Tuberculosis and Treatment with Infliximab N. Engl. J. Med., February 21, 2002; 346(8): 623 - 626. [Full Text] [PDF]
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M. Engele, K. Castiglione, N. Schwerdtner, M. Wagner, P. Bolcskei, M. Rollinghoff, and S. Stenger Induction of TNF in Human Alveolar Macrophages As a Potential Evasion Mechanism of Virulent Mycobacterium tuberculosis J. Immunol., February 1, 2002; 168(3): 1328 - 1337. [Abstract] [Full Text] [PDF]
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N. P. Juffermans, J. C. Leemans, S. Florquin, A. Verbon, A. H. Kolk, P. Speelman, S. J. H. van Deventer, and T. van der Poll CpG Oligodeoxynucleotides Enhance Host Defense during Murine Tuberculosis Infect. Immun., January 1, 2002; 70(1): 147 - 152. [Abstract] [Full Text] [PDF]
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W. Peters, H. M. Scott, H. F. Chambers, J. L. Flynn, I. F. Charo, and J. D. Ernst Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis PNAS, July 3, 2001; 98(14): 7958 - 7963. [Abstract] [Full Text] [PDF]
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J. L. Flynn and J. Chan Tuberculosis: Latency and Reactivation Infect. Immun., July 1, 2001; 69(7): 4195 - 4201. [Full Text] [PDF]
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Z. Xing, A. Zganiacz, J. Wang, and S. K. Sharma Enhanced Protection Against Fatal Mycobacterial Infection in SCID Beige Mice by Reshaping Innate Immunity with IFN-{{gamma}} Transgene J. Immunol., July 1, 2001; 167(1): 375 - 383. [Abstract] [Full Text] [PDF]
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L.-G. Bekker, S. Freeman, P. J. Murray, B. Ryffel, and G. Kaplan TNF-{{alpha}} Controls Intracellular Mycobacterial Growth by Both Inducible Nitric Oxide Synthase-Dependent and Inducible Nitric Oxide Synthase-Independent Pathways J. Immunol., June 1, 2001; 166(11): 6728 - 6734. [Abstract] [Full Text] [PDF]
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N. Boechat, F. Bouchonnet, M. Bonay, A. Grodet, V. Pelicic, B. Gicquel, and A. J. Hance Culture at High Density Improves the Ability of Human Macrophages to Control Mycobacterial Growth J. Immunol., May 15, 2001; 166(10): 6203 - 6211. [Abstract] [Full Text] [PDF]
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C. Demangel, U. Palendira, C. G. Feng, A. W. Heath, A. G. D. Bean, and W. J. Britton Stimulation of Dendritic Cells via CD40 Enhances Immune Responses to Mycobacterium tuberculosis Infection Infect. Immun., April 1, 2001; 69(4): 2456 - 2461. [Abstract] [Full Text] [PDF]
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C. Ameixa and J. S. Friedland Down-Regulation of Interleukin-8 Secretion from Mycobacterium tuberculosis-Infected Monocytes by Interleukin-4 and -10 but Not by Interleukin-13 Infect. Immun., April 1, 2001; 69(4): 2470 - 2476. [Abstract] [Full Text] [PDF]
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P. Wilhelm, U. Ritter, S. Labbow, N. Donhauser, M. Rollinghoff, C. Bogdan, and H. Korner Rapidly Fatal Leishmaniasis in Resistant C57BL/6 Mice Lacking TNF J. Immunol., March 15, 2001; 166(6): 4012 - 4019. [Abstract] [Full Text] [PDF]
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T. K. Means, B. W. Jones, A. B. Schromm, B. A. Shurtleff, J. A. Smith, J. Keane, D. T. Golenbock, S. N. Vogel, and M. J. Fenton Differential Effects of a Toll-Like Receptor Antagonist on Mycobacterium tuberculosis-Induced Macrophage Responses J. Immunol., March 15, 2001; 166(6): 4074 - 4082. [Abstract] [Full Text] [PDF]
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F. A. Post, C. Manca, O. Neyrolles, B. Ryffel, D. B. Young, and G. Kaplan Mycobacterium tuberculosis 19-Kilodalton Lipoprotein Inhibits Mycobacterium smegmatis-Induced Cytokine Production by Human Macrophages In Vitro Infect. Immun., March 1, 2001; 69(3): 1433 - 1439. [Abstract] [Full Text] [PDF]
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V. P. Mohan, C. A. Scanga, K. Yu, H. M. Scott, K. E. Tanaka, E. Tsang, M. C. Tsai, J. L. Flynn, and J. Chan Effects of Tumor Necrosis Factor Alpha on Host Immune Response in Chronic Persistent Tuberculosis: Possible Role for Limiting Pathology Infect. Immun., March 1, 2001; 69(3): 1847 - 1855. [Abstract] [Full Text] [PDF]
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J. E. Wigginton and D. Kirschner A Model to Predict Cell-Mediated Immune Regulatory Mechanisms During Human Infection with Mycobacterium tuberculosis J. Immunol., February 1, 2001; 166(3): 1951 - 1967. [Abstract] [Full Text] [PDF]
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D. R. Roach, H. Briscoe, B. Saunders, M. P. France, S. Riminton, and W. J. Britton Secreted Lymphotoxin-{alpha} Is Essential for the Control of an Intracellular Bacterial Infection J. Exp. Med., January 15, 2001; 193(2): 239 - 246. [Abstract] [Full Text] [PDF]
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A. M. Cooper, J. E. Pearl, J. V. Brooks, S. Ehlers, and I. M. Orme Expression of the Nitric Oxide Synthase 2 Gene Is Not Essential for Early Control of Mycobacterium tuberculosis in the Murine Lung Infect. Immun., December 1, 2000; 68(12): 6879 - 6882. [Abstract] [Full Text] [PDF]
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L.-G. Bekker, A. L. Moreira, A. Bergtold, S. Freeman, B. Ryffel, and G. Kaplan Immunopathologic Effects of Tumor Necrosis Factor Alpha in Murine Mycobacterial Infection Are Dose Dependent Infect. Immun., December 1, 2000; 68(12): 6954 - 6961. [Abstract] [Full Text] [PDF]
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H. W. Murray, A. Jungbluth, E. Ritter, C. Montelibano, and M. W. Marino Visceral Leishmaniasis in Mice Devoid of Tumor Necrosis Factor and Response to Treatment Infect. Immun., November 1, 2000; 68(11): 6289 - 6293. [Abstract] [Full Text] [PDF]
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H. Briscoe, D. R. Roach, N. Meadows, D. Rathjen, and W. J. Britton A novel tumor necrosis factor (TNF) mimetic peptide prevents recrudescence of Mycobacterium bovis bacillus Calmette-Guerin (BCG) infection in CD4+ T cell-depleted mice J. Leukoc. Biol., October 1, 2000; 68(4): 538 - 544. [Abstract] [Full Text]
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