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Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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receptors on inflammatory macrophages to preferentially induce the
production of high amounts of IL-10. The IL-10 produced by infected
macrophages prevented macrophage activation and diminished their
production of IL-12 and TNF-
. In vitro survival assays confirmed the
importance of IL-10 in preventing parasite killing by activated
macrophages. Pretreatment of monolayers with either rIL-10 or
supernatants from amastigote-infected macrophages resulted in a
dramatic enhancement in parasite intracellular survival. These studies
indicate that amastigotes of Leishmania use an unusual
and unexpected virulence factor, host IgG. This IgG allows amastigotes
to exploit the antiinflammatory effects of FcR ligation to induce
the production of IL-10, which renders macrophages refractory to the
activating effects of IFN-. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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is
produced during visceral leishmaniasis caused by Leishmania
donovani (4, 5). Despite the presence of high levels
of IFN-, infected hosts generally fail to control the infection and
resolve their disease. In fact in humans, the severity of visceral
leishmaniasis has been most closely associated with increased levels of
IL-10 (5, 6, 7). IL-10 production also correlated with lesion
progression in patients with cutaneous leishmaniasis (8).
A similar correlation has recently been made in IL-10-transgenic mice,
which are susceptible to progressive L. major disease
despite producing IFN- (9). These and other studies
point to an important role for IL-10 in regulating immune responses
to this intracellular pathogen. There are two developmental forms of Leishmania: the promastigote and the amastigote (10). The promastigote is introduced into the mammalian host when an infected sandfly takes a bloodmeal. This form is taken up by phagocytic cells and rapidly transforms into the amastigote form. Amastigotes replicate intracellularly within mononuclear phagocytes and are the only form found within the mammalian host following infection. The unexpected observation was made several years ago that Leishmania amastigotes have host-derived IgG on their surface (11, 12). This observation was recently confirmed, and the role of IgG as an opsonin for enhanced parasite adhesion to macrophages was proposed (13). We have previously shown that Leishmania amastigotes bind avidly to mammalian cell proteoglycans (14), and do not require opsonization for parasite adhesion to macrophages. We therefore began to look for alternative functions for Ig on the amastigote surface to explain the enhanced virulence of IgG-opsonized amastigotes.
We have recently demonstrated that the ligation of phagocytic receptors
on macrophages can alter their cytokine profile when these cells are
exposed to a variety of inflammatory stimuli (15, 16). We
showed that the ligation of the FcR by immune complexes was a
particularly potent way to prevent the production of proinflammatory
cytokines. The ligation of this receptor class not only inhibited the
production of IL-12 (15), but unlike complement receptor
ligation, FcR ligation also induced the synthesis and secretion of
IL-10 (16). IL-10 production occurred only in cells
containing a functional FcR -chain, indicating that FcR signaling
through the -chain was required for IL-10 production. We proposed
that this antiinflammatory cytokine milieu would have the potential to
inhibit the production of a type 1 immune response and prevent
macrophage activation. Consistent with this hypothesis is the
observation by others that the administration of immune complexes to
mice prevented effective cellular responses to Listeria
monocytogenes and diminished bacterial clearance
(17).
In the present study, we examined cytokine production by macrophages
following their interaction with Leishmania amastigotes. We
show that lesion-derived amastigotes induce the robust production of
IL-10 from stimulated macrophages. The molecule responsible for this
induction is host IgG on the amastigote surface, which ligates
macrophage FcRs. The IL-10 that is produced by this mechanism
inhibits macrophage activation and contributes to parasite growth in
lesions. Thus, we have identified an unexpected Leishmania
virulence factor: host IgG.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6, C3H/HeJ, and BALB/c mice were obtained from The Jackson
Laboratory (Bar Harbor, ME). IL-10-/- mice on a
BALB/c background were kindly provided by Donna Rennick, DNAX (Palo
Alto, CA). IL-10-/- mice were maintained under
germfree conditions in the Barrier Animal Facility of Temple University
in MicroFlow System ventilated cages (Allentown Caging Equipment,
Allentown, PA). Breeding pairs of FcR -chain knockout mice
(-/-) (18) were purchased from
Taconic Farms (Germantown, NY).
Parasites
A clone of L. major (WHO MHOM/IL/80/Friedlin) and the Josefa isolate of Leishmania mexicana amazonensis (14) were used for these studies. Promastigotes were grown in Schneider’s insect cell culture medium (Life Technologies, Grand Island, NY) supplemented with 20% heat-inactivated FBS, 2 mM glutamine, 100 U/ml penicillin G, and 100 µg/ml streptomycin. Axenic L. mexicana amazonensis amastigotes were grown at 32°C, as previously described (19). Lesion-derived amastigotes were isolated from BALB/c mice infected 6–8 wk before as described previously (20).
Macrophages
Bone marrow-derived macrophages
(BMM
)3 were established as previously
described (15). Murine peritoneal macrophages were washed
from the peritoneal cavity of either C57BL/6 or BALB/c mice as
described elsewhere (21). Cells were cultivated in DMEM
containing 10% heat-inactivated FBS, 2 mM glutamine, 100 U/ml
penicillin G, and 100 µg/ml streptomycin (complete medium)
(D-10).
Macrophage stimulation and receptor ligation
BMM were used to measure the production of cytokines. Cells
were seeded overnight in 24-well plates in complete medium at a density
of 2 x 105 cells/well. Cells were washed
once with complete medium, and then stimuli were added to induce
cytokine production. Lesion amastigotes and axenic amastigotes were
added at a ratio of 10 amastigotes per macrophage. Amastigotes were
added either alone or simultaneously with either LPS (Escherichia
coli 0128.B12; Sigma, St. Louis, MO) or low molecular weight
hyaluronic acid (HA; ICN Biomedicals, Costa Mesa, CA) at concentrations
indicated in the figure legends.
Macrophage activation in vitro
BMM were activated by pretreating them overnight with 250
U/ml IFN- (R&D Systems, Minneapolis, MN) and 100 ng/ml LPS. For in
vitro leishmanicidal assays, peritoneal macrophages were pretreated
with either 10 ng/ml rIL-10 (R&D Systems) or supernatants from
stimulated macrophages infected with Leishmania amastigotes
(infected macrophage supernatants) 3 h before activation with
IFN-. Three hours later, L. major amastigotes were added
to macrophage monolayers at a 3:1 (parasite:macrophage) ratio for
72 h at 35°C. Nonphagocytozed amastigotes were washed from the
cultures at 24 h postinfection, and fresh medium was added to each
well with the appropriate cytokine conditions for an additional 48
h. At the termination of the incubation period, the wells were washed
once with complete medium, then fixed with 100% methanol at 4°C for
30 min. The monolayers were washed with PBS containing 5% FCS
(PBS/FCS) and processed for immunofluorescent staining to visualize
intracellular Leishmania amastigotes. Murine polyclonal
anti-leishmania antiserum was used as the primary Ab, and goat
-murine-IgG conjugated with FITC was used as the secondary Ab, as
described previously (20). Coverslips were counterstained
with propidium iodide and examined by fluorescence microscopy.
Flow cytometry
Footpad lesion amastigotes were isolated from BALB/c mice
infected 6–8 wk, as described previously (20). To
directly stain murine IgG on the amastigote surface, 1 x
106 amastigotes were incubated on ice for 30 min
with FITC-conjugated goat anti-murine (Fc chain-specific) IgG
(Jackson ImmunoResearch,West Grove, PA) diluted 1/100 in PBS/FCS.
Amastigotes were opsonized with IgG by incubating them on ice for 30
min with a 1/10 dilution of serum from a mouse infected with viable
Leishmania. Following three washes in PBS/FCS to remove
nonspecific IgG, FITC-conjugated goat anti-murine IgG was added on
ice for an additional 30 min. The amastigotes were washed and fixed in
1% paraformaldehyde and immediately analyzed on an Epics Elite flow
cytometer (Coulter Diagnostics, Hialeah, FL).
Cytokine ELISAs
Culture supernatants from monolayers of control and stimulated macrophages were assayed by ELISA for cytokine production 20–24 h after stimulation. Murine IL-10 production was measured as previously described (16) using mAbs to IL-10, JES5-2A5, and biotinylated JES5-16E3 (PharMingen, San Diego, CA). IL-12 (p70) levels were measured using mAbs C18.2 (IL-12 p35) and biotinylated C17.15 (IL-12 p40) as described elsewhere (16). TNF production was measured using mAbs G281-2626 and biotinylated MP6-XT3 (PharMingen).
Parasite quantitation
Mice were injected in the hind footpad with 2 x 106 L. major amastigotes. Parasite burdens in footpads were determined by a limiting serial dilution of single cell suspensions made from individual excised lesions as described reviously (22). Lesion size was determined by measuring the thickness of the footpad with a caliper, and subtracting the thickness of the uninfected contralateral footpad.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To determine the effect of IL-10 on disease progression in
leishmaniasis, we infected mice deficient in IL-10 on a BALB/c
background and compared them with wild-type mice. BALB/c mice are
genetically susceptible to L. major infection
(3), and therefore wild-type mice produce progressive
nonhealing lesions (Fig. 1
A)
that increased in size until day 36, when the lesions began to ulcerate
and metastasize. On day 36, there were in excess of 1 x
109 organisms per infected footpad (Fig. 1B). For humane reasons, these mice were euthanized at this
time. In contrast to wild-type BALB/c mice, congenic mice lacking IL-10
were relatively resistant to infection, showing only modest increases
in lesion size through the 11-wk observation period (Fig. 1A). At 2 wk postinfection, a time when footpad swelling in
the two groups had not yet begun to exhibit differences, mice lacking
IL-10 already had 
100-fold fewer parasites in their lesions than
wild-type mice (Fig. 1B). By the fifth week,
IL-10-/- mice had 1000-fold fewer organisms in
their lesions, and by the 11 wk only 100 organisms could be detected
per infected foot in IL-10-/- mice (103 ±
128). Thus, mice lacking IL-10 are relatively resistant to
Leishmania infection.
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Previous studies have demonstrated that lesion-derived amastigotes
have host IgG on their surface (11, 12, 13). To confirm these
observations, flow cytometry was performed to identify host IgG on the
surface of lesion-derived amastigotes. Amastigotes were isolated from
the footpads of infected BALB/c mice and directly stained with
FITC-conjugated Ab to the Fc fragment of murine IgG (Fig. 2
, open histograms). By flow cytometry,
lesion-derived amastigotes stained positively for murine IgG (Fig. 2, right). Virtually all of the organisms in the population
were positive for surface Ig, and the majority expressed relatively
high levels of IgG with a mean fluorescence intensity of over 10. In
contrast, axenic amastigotes grown in vitro in the absence of IgG were
devoid of surface IgG (Fig. 2, left). Their mean
fluorescence intensity was not substantially different from unstained
organisms (gray histograms). Preincubation of these organisms with
antiserum to amastigotes as the primary Ab, followed by the FITC
anti-IgG (filled histograms), resulted in axenic amastigotes
staining positively for murine IgG (Fig. 1
, left).
Similarly, staining footpad amastigotes with primary Ab followed by
FITC anti-IgG also resulted in positive staining. This staining was
only slightly higher than lesion-derived amastigotes stained with
secondary Ab alone. Thus, these data confirm previous observations
(11) that lesion-derived amastigotes have host IgG on
their surface, and they also demonstrate that axenic organisms do
not.
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Macrophage IL-10 production was measured following infection of
BMM with Leishmania amastigotes. To induce cytokine
production in these assays, BMM were exposed in vitro to subnanogram
amounts of bacterial LPS. The low levels of LPS used in these assays
(125–500 pg/ml) did not induce detectable levels of IL-10. However,
the simultaneous addition of L. major amastigotes to these
cells induced the secretion of large amounts of IL-10 (Fig. 3A). The induction of IL-10 by
lesion-derived amastigotes required the presence of a costimulus, such
as LPS, since washed amastigotes alone, (even when added at high
multiplicities of infection; not shown), were unable to induce
significant IL-10 production from BMM (Fig. 3A).
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from C3H/HeJ mice, which are hyporesponsive to LPS, were exposed
to low molecular weight HA, a matrix component that is present in
inflamed tissue (24). These cells were infected with
Leishmania amastigotes, and cytokine production was
measured. Similar to LPS, HA alone induced little or no IL-10, but the
combination of HA with amastigote infection induced a robust production
of IL-10 (Fig. 3B). Thus, a stimuli that is present in
inflamed lesions induces IL-10 production from macrophages when they
encounter Leishmania amastigotes.
To determine whether the IgG on the surface of amastigotes was required
for IL-10 induction, macrophages were infected with axenically grown
amastigotes (AA) that lack surface IgG (see Fig. 2). These organisms
failed to up-regulate macrophage IL-10 production from stimulated
macrophages (Fig. 4A). The
opsonization of axenic amastigotes with immune serum (IgG-AA), however,
induced high levels of IL-10 from wild-type macrophages (Fig. 4A, filled bars). The failure of unopsonized axenic
amastigotes to induce IL-10 was not due to a failure of these organisms
to bind to or invade macrophages, since axenic amastigotes attach to
and invade host macrophages nearly as well as IgG-opsonized organisms
(data not shown). Thus, amastigotes of two different species of
Leishmania, L. major (Fig. 3) and L.
amazonensis (Fig. 4), induced IL-10 production from inflammatory
macrophages.
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R ligation
could induce the secretion of IL-10 from stimulated macrophages
(16). To show that the present effect was a result of
FcR ligation, cytokine production by macrophages from mice lacking
the -chain of the FcR (-/-) was
analyzed. Unlike wild-type cells, macrophages from
-/- mice failed to up-regulate IL-10 when
infected with axenic amastigotes opsonized with IgG (Fig. 4A, gray bars). The failure to produce IL-10 by
-/- macrophages is consistent with our
previous studies showing a requirement for -chain signaling in
inducing macrophage IL-10 production following FcR ligation
(16). Similar studies were performed on
-/- macrophages infected with lesion-derived
amastigotes rather than axenic amastigotes (Fig. 4B).
Amastigotes derived from lesions of infected mice induced some IL-10
production from stimulated -/- macrophages
in vitro (Fig. 4B, gray bars). These levels, however, were
much lower than those produced by parallel monolayers of wild-type
macrophages (Fig. 4B, filled bars). Thus, maximal IL-10
production by macrophages infected with Leishmania
amastigotes requires FcR ligation along with a second costimulatory
signal, such as bacterial products or components of the extracellular
matrix.
IL-10 induced from infected macrophages suppresses the production
of IL-12 (p70), and TNF- by IFN-/LPS-activated macrophages
To examine the biological consequences of macrophage IL-10
production, supernatants from amastigote-infected macrophages were
added to monolayers of uninfected BMM, which were then stimulated
with IFN-/LPS. Control monolayers of BMM that were activated with
IFN-/LPS secreted relatively large amounts of IL-12 (p70) (Fig. 5A) and TNF- (Fig. 5B). The addition of supernatants from amastigote-infected
monolayers to cells prevented IL-12 production in a dose-dependent
manner (Fig. 5A). Stimulated macrophages produced 1 ng/ml
of IL-12 (p70), and this production was inhibited to undetectable
levels by the addition of 30% (v/v) amastigote supernatants (Fig. 5A). The inhibition of IL-12 (p70) depended on the presence
of IL-10 in these supernatants because pretreatment of the supernatants
with a blocking mAb to IL-10 completely abrogated this suppression,
restoring IL-12 production to control levels (Fig. 5A).
Parallel studies were performed to analyze TNF- production by
macrophages exposed to supernatants from infected macrophages. In vitro
activation with IFN-/LPS caused a marked increase in TNF-
production by macrophages, and treatment of macrophages with either
rIL-10 or supernatants from amastigote-infected monolayers dramatically
inhibited macrophage TNF- production (Fig. 5B). These
results indicate that IL-10 produced by amastigote-infected
inflammatory macrophages is adequate to inhibit the production of both
IL-12 and TNF- by stimulated macrophages.
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BALB/c peritoneal macrophages were infected with L.
major amastigotes in vitro, and their survival was measured over a
72-h interval. Parasite survival in resident (untreated) cells was
compared with survival in activated cells. Some of the monolayers were
pretreated with either rIL-10 or supernatants from amastigote-infected
macrophages for 2 h before the addition of IFN-. Untreated
cells, as expected, were unable to restrict parasite growth and allowed
uncontrolled intracellular replication of amastigotes. By 72 h
postinfection, the majority of infected cells had five or more
organisms within them (Fig. 6, A and E). In contrast to the resident cells,
macrophages activated in vitro with IFN- were able to restrict the
intracellular growth of Leishmania (Fig. 6B).
Most of the cells in the population had completely cleared their
infection (Fig. 6B) and few if any of the cells contained
five or more organisms within them (Fig. 6E). Pretreatment
of cells with rIL-10 before the addition of IFN- prevented optimal
activation (25, 26) and resulted in uncontrolled parasite
replication (Fig. 6B). The majority of cells were infected
and a significant percentage of the cells contained five or more
parasites within them (Fig. 6E). Monolayers were also
pretreated with 10% (v/v) supernatants from amastigote-infected
macrophages. Similar to rIL-10, these supernatants prevented macrophage
responses to IFN- and allowed uncontrolled intracellular replication
of parasites (Fig. 6, D and E). Thus,
pretreatment of macrophages with either IL-10 or supernatants from
infected monolayers prevented them from responding to IFN- and
restricting the intracellular growth of parasites.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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These results differ from the phenotype observed in mice treated with anti-IL-10 Ab during infection with L. major (27), which showed only a minimal phenotype. Another study used an IL-10-transgenic mouse model in which the IL-10 transgene was under the control of the IL-2 promoter (28), and these IL-10-transgenic mice had no change in their response to Leishmania infection compared with control mice. These and other studies suggested that IL-10 was not a key regulator in Leishmania infection, and that IL-10 did not play a role in T cell subset development (27, 29). Recent studies (9), however, have examined the role of IL-10 in IL-10-transgenic mice, in which the IL-10 gene was under the control of the MHC class II Ea promoter. These mice had a profound phenotype and were highly susceptible to L. major infection. The susceptible phenotype of these transgenic mice indicates that the immunosuppressive activity of IL-10 on the macrophage/monocyte population contributes to disease progression in leishmaniasis. Our model using IL-10 knockout mice supports these later observations and further clarifies the role of IL-10 in contributing to uncontrolled intracellular parasite growth. Studies to identify alterations in macrophage function in response to IL-10 are ongoing.
Our in vitro data indicate that macrophage IL-10 is being turned on
by the amastigote itself. We have previously demonstrated that the
ligation of FcR on stimulated macrophages can induce the production
of IL-10 in vitro (16). We now show that
Leishmania amastigotes exploit this mechanism to produce
IL-10 production from infected macrophages. There are several lines of
evidence that indicate that IL-10 production was a consequence of the
ligation of macrophage FcRs by amastigotes. First, axenic
amastigotes grown in the absence of IgG failed to induce IL-10 unless
they were opsonized with immune IgG, in which case their inducing
capacity was fully restored. Second, macrophages lacking the common
-chain of the FcRs produced less IL-10 following infection than
did parallel monolayers of normal macrophages. Thus, optimal IL-10
production in this system depended on FcR ligation. We note that the
low levels of IL-10 induced by lesion-derived amastigotes from
-/- macrophages (Fig. 4B) suggest
that the ligation of other macrophage receptors by amastigotes may
(minimally) also contribute to IL-10 induction. Thus, although FcR
ligation may not be required for IL-10 production, it is a major
contributing factor.
Receptor ligation alone, however, was not sufficient to induce IL-10 production. Low levels of costimulation with either low molecular weight HA or LPS were also required. These costimuli may be physiologically relevant because both have the potential to be present in Leishmania lesions. Cutaneous lesions in patients and experimentally infected animals are frequently superinfected with bacteria (23), and HA is ubiquitous in inflamed tissue (24). Current studies are underway to define other costimulatory stimuli, such as chemokine stimulation, that may cooperate with receptor ligation to induce IL-10 production.
The present studies may provide a partial explanation for two recent
observations showing that mice lacking IgG or FcRs are actually more
resistant to Leishmania infection. Working in a cutaneous
model of L. amazonensis infection, Kima and colleagues
(30) showed that the common -chain of the FcR was
required for optimal lesion progression in mice. These results support
our hypothesis that IgG-opsonized amastigotes use Fc receptors during
infection to enhance macrophage IL-10 production. Smelt and colleagues
(31) have shown that visceral infection with L.
donovani was diminished in mice lacking IgG. This observation
would also be consistent with a role for IgG-induced IL-10 in
contributing to lesion progression during leishmaniasis.
We examined the consequences of macrophage IL-10 production by
adding supernatants from amastigote-infected macrophages to naive
monolayers, which were then exposed to IFN-/LPS. Supernatants
from infected monolayers inhibited the activation of macrophages
exposed to IFN-/LPS. These treated macrophages produced
significantly less TNF-, and they were virtually unable to produce
IL-12. Importantly, these pretreated monolayers failed to control
Leishmania infection. The majority of the cells in the
monolayer were infected, and most of the cells had multiple organisms
growing within them (Fig. 6, D–E). Thus, a prior encounter
with IL-10 renders macrophages refractory to the activating effects of
IFN- and prevents them from eliminating intracellular parasites, as
previously reported (26).
In summary, we have examined the interaction of Leishmania
amastigotes with tissue macrophages and have identified an unexpected
role for host IgG. Rather than simply acting as a classical opsonin to
accelerate parasite phagocytosis, an additional role of surface IgG is
to induce the production of IL-10 by macrophages. This induction
prevents these cells from responding to IFN- and eliminating
intracellular parasites. This work suggests that an important way that
Leishmania parasites modify the host immune response is by
exploiting the antiinflammatory effects of FcR ligation to induce
the production of IL-10.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. David M. Mosser, Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, MD 20742.
3 Abbreviations used in this paper: BMM, bone marrow-derived macrophages; AA, axenically grown amastigotes; HA, hyaluronic acid.
Received for publication May 9, 2000. Accepted for publication October 13, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 M. A. Al-Wabel, W. K. Tonui, L. Cui, S. K. Martin, and R. G. Titus Protection of Susceptible BALB/c Mice from Challenge with Leishmania major by Nucleoside Hydrolase, a Soluble Exo-antigen of Leishmania Am J Trop Med Hyg, December 1, 2007; 77(6): 1060 - 1065. [Abstract] [Full Text] [PDF]
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G. Xu, D. Liu, Y. Fan, X. Yang, H. Korner, Y.-X. Fu, and J. E. Uzonna Lymphotoxin {alpha}beta2 (Membrane Lymphotoxin) Is Critically Important for Resistance to Leishmania major Infection in Mice J. Immunol., October 15, 2007; 179(8): 5358 - 5366. [Abstract] [Full Text] [PDF]
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H. Nagase, K. M. Jones, C. F. Anderson, and N. Noben-Trauth Despite Increased CD4+Foxp3+ Cells within the Infection Site, BALB/c IL-4 Receptor-Deficient Mice Reveal CD4+Foxp3-Negative T Cells as a Source of IL-10 in Leishmania major Susceptibility J. Immunol., August 15, 2007; 179(4): 2435 - 2444. [Abstract] [Full Text] [PDF]
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N. Wanasen, C. L. MacLeod, L. G. Ellies, and L. Soong L-Arginine and Cationic Amino Acid Transporter 2B Regulate Growth and Survival of Leishmania amazonensis Amastigotes in Macrophages Infect. Immun., June 1, 2007; 75(6): 2802 - 2810. [Abstract] [Full Text] [PDF]
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L. M. Johnson and P. Scott STAT1 Expression in Dendritic Cells, but Not T Cells, Is Required for Immunity to Leishmania major J. Immunol., June 1, 2007; 178(11): 7259 - 7266. [Abstract] [Full Text] [PDF]
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T. M. Brodie, M. C. Smith, R. V. Morris, and R. G. Titus Immunomodulatory Effects of the Lutzomyia longipalpis Salivary Gland Protein Maxadilan on Mouse Macrophages Infect. Immun., May 1, 2007; 75(5): 2359 - 2365. [Abstract] [Full Text] [PDF]
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R. M. MUKBEL, C. PATTEN JR., K. GIBSON, M. GHOSH, C. PETERSEN, and D. E. JONES MACROPHAGE KILLING OF LEISHMANIA AMAZONENSIS AMASTIGOTES REQUIRES BOTH NITRIC OXIDE AND SUPEROXIDE Am J Trop Med Hyg, April 1, 2007; 76(4): 669 - 675. [Abstract] [Full Text] [PDF]
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 C. F. Anderson, M. Oukka, V. J. Kuchroo, and D. Sacks CD4+CD25-Foxp3- Th1 cells are the source of IL-10-mediated immune suppression in chronic cutaneous leishmaniasis J. Exp. Med., February 19, 2007; 204(2): 285 - 297. [Abstract] [Full Text] [PDF]
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Z. Yang, D. M. Mosser, and X. Zhang Activation of the MAPK, ERK, following Leishmania amazonensis Infection of Macrophages J. Immunol., January 15, 2007; 178(2): 1077 - 1085. [Abstract] [Full Text] [PDF]
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M. C. MONTEIRO, H. C. LIMA, A. A. A. SOUZA, R. G. TITUS, P. R. T. ROMAO, and F. DE QUEIROZ CUNHA EFFECT OF LUTZOMYIA LONGIPALPIS SALIVARY GLAND EXTRACTS ON LEUKOCYTE MIGRATION INDUCED BY LEISHMANIA MAJOR Am J Trop Med Hyg, January 1, 2007; 76(1): 88 - 94. [Abstract] [Full Text] [PDF]
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R. E. Vasquez and L. Soong CXCL10/Gamma Interferon-Inducible Protein 10-Mediated Protection against Leishmania amazonensis Infection in Mice Infect. Immun., December 1, 2006; 74(12): 6769 - 6777. [Abstract] [Full Text] [PDF]
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J. M. Spera, J. E. Ugalde, J. Mucci, D. J. Comerci, and R. A. Ugalde A B lymphocyte mitogen is a Brucella abortus virulence factor required for persistent infection PNAS, October 31, 2006; 103(44): 16514 - 16519. [Abstract] [Full Text] [PDF]
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E. Yurchenko, M. Tritt, V. Hay, E. M. Shevach, Y. Belkaid, and C. A. Piccirillo CCR5-dependent homing of naturally occurring CD4+ regulatory T cells to sites of Leishmania major infection favors pathogen persistence J. Exp. Med., October 30, 2006; 203(11): 2451 - 2460. [Abstract] [Full Text] [PDF]
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X. Sun, H. P. Jones, L. M. Hodge, and J. W. Simecka Cytokine and Chemokine Transcription Profile during Mycoplasma pulmonis Infection in Susceptible and Resistant Strains of Mice: Macrophage Inflammatory Protein 1{beta} (CCL4) and Monocyte Chemoattractant Protein 2 (CCL8) and Accumulation of CCR5+ Th Cells. Infect. Immun., October 1, 2006; 74(10): 5943 - 5954. [Abstract] [Full Text] [PDF]
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 S. Cao, X. Zhang, J. P. Edwards, and D. M. Mosser NF-{kappa}B1 (p50) Homodimers Differentially Regulate Pro- and Anti-inflammatory Cytokines in Macrophages J. Biol. Chem., September 8, 2006; 281(36): 26041 - 26050. [Abstract] [Full Text] [PDF]
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 M. T. M. Roberts Current understandings on the immunology of leishmaniasis and recent developments in prevention and treatment Br. Med. Bull., July 17, 2006; 75-76(1): 115 - 130. [Abstract] [Full Text] [PDF]
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P. M. Gray, S. L. Reiner, D. F. Smith, P. M. Kaye, and P. Scott Antigen-Experienced T Cells Limit the Priming of Naive T Cells during Infection with Leishmania major J. Immunol., July 15, 2006; 177(2): 925 - 933. [Abstract] [Full Text] [PDF]
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X. Zhang, J. P. Edwards, and D. M. Mosser Dynamic and Transient Remodeling of the Macrophage IL-10 Promoter during Transcription J. Immunol., July 15, 2006; 177(2): 1282 - 1288. [Abstract] [Full Text] [PDF]
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M. H. Shaw, G. J. Freeman, M. F. Scott, B. A. Fox, D. J. Bzik, Y. Belkaid, and G. S. Yap Tyk2 Negatively Regulates Adaptive Th1 Immunity by Mediating IL-10 Signaling and Promoting IFN-{gamma}-Dependent IL-10 Reactivation. J. Immunol., June 15, 2006; 176(12): 7263 - 7271. [Abstract] [Full Text] [PDF]
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 C. Zhao, S. Thibault, N. Messier, M. Ouellette, B. Papadopoulou, and M. J. Tremblay In primary human monocyte-derived macrophages exposed to Human immunodeficiency virus type 1, does the increased intracellular growth of Leishmania infantum rely on its enhanced uptake? J. Gen. Virol., May 1, 2006; 87(Pt 5): 1295 - 1302. [Abstract] [Full Text] [PDF]
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F. Woelbing, S. L. Kostka, K. Moelle, Y. Belkaid, C. Sunderkoetter, S. Verbeek, A. Waisman, A. P. Nigg, J. Knop, M. C. Udey, et al. Uptake of Leishmania major by dendritic cells is mediated by Fc{gamma} receptors and facilitates acquisition of protective immunity J. Exp. Med., January 23, 2006; 203(1): 177 - 188. [Abstract] [Full Text] [PDF]
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M. D. Woolard, D. Hudig, L. Tabor, J. A. Ivey, and J. W. Simecka NK Cells in Gamma-Interferon-Deficient Mice Suppress Lung Innate Immunity against Mycoplasma spp. Infect. Immun., October 1, 2005; 73(10): 6742 - 6751. [Abstract] [Full Text] [PDF]
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U. M. Padigel and J. P. Farrell Control of Infection with Leishmania major in Susceptible BALB/c Mice Lacking the Common {gamma}-Chain for FcR Is Associated with Reduced Production of IL-10 and TGF-{beta} by Parasitized Cells J. Immunol., May 15, 2005; 174(10): 6340 - 6345. [Abstract] [Full Text] [PDF]
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S. Yoshizawa, K. Tateda, T. Matsumoto, F. Gondaira, S. Miyazaki, T. J. Standiford, and K. Yamaguchi Legionella pneumophila Evades Gamma Interferon-Mediated Growth Suppression through Interleukin-10 Induction in Bone Marrow-Derived Macrophages Infect. Immun., May 1, 2005; 73(5): 2709 - 2717. [Abstract] [Full Text] [PDF]
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L. U. Buxbaum and P. Scott Interleukin 10- and Fc{gamma} Receptor-Deficient Mice Resolve Leishmania mexicana Lesions Infect. Immun., April 1, 2005; 73(4): 2101 - 2108. [Abstract] [Full Text] [PDF]
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S. A. Miles, S. M. Conrad, R. G. Alves, S. M.B. Jeronimo, and D. M. Mosser A role for IgG immune complexes during infection with the intracellular pathogen Leishmania J. Exp. Med., March 7, 2005; 201(5): 747 - 754. [Abstract] [Full Text] [PDF]
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C. F. Anderson, S. Mendez, and D. L. Sacks Nonhealing Infection despite Th1 Polarization Produced by a Strain of Leishmania major in C57BL/6 Mice J. Immunol., March 1, 2005; 174(5): 2934 - 2941. [Abstract] [Full Text] [PDF]
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Y. VANLOUBBEECK and D. E. JONES PROTECTION OF C3HEB/FEJ MICE AGAINST LEISHMANIA AMAZONENSIS CHALLENGE AFTER PREVIOUS LEISHMANIA MAJOR INFECTION Am J Trop Med Hyg, October 1, 2004; 71(4): 407 - 411. [Abstract] [Full Text] [PDF]
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P. Cameron, A. McGachy, M. Anderson, A. Paul, G. H. Coombs, J. C. Mottram, J. Alexander, and R. Plevin Inhibition of Lipopolysaccharide-Induced Macrophage IL-12 Production by Leishmania mexicana Amastigotes: The Role of Cysteine Peptidases and the NF-{kappa}B Signaling Pathway J. Immunol., September 1, 2004; 173(5): 3297 - 3304. [Abstract] [Full Text] [PDF]
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B. E. C. Babay, H. Louzir, C. Kebaier, S. Boubaker, K. Dellagi, and P.-A. Cazenave Inbred Strains Derived from Feral Mice Reveal New Pathogenic Mechanisms of Experimental Leishmaniasis Due to Leishmania major Infect. Immun., August 1, 2004; 72(8): 4603 - 4611. [Abstract] [Full Text] [PDF]
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P. A. Darrah, M. C. G. Monaco, S. Jain, M. K. Hondalus, D. T. Golenbock, and D. M. Mosser Innate Immune Responses to Rhodococcus equi J. Immunol., August 1, 2004; 173(3): 1914 - 1924. [Abstract] [Full Text] [PDF]
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S. Mendez, S. K. Reckling, C. A. Piccirillo, D. Sacks, and Y. Belkaid Role for CD4+ CD25+ Regulatory T Cells in Reactivation of Persistent Leishmaniasis and Control of Concomitant Immunity J. Exp. Med., July 19, 2004; 200(2): 201 - 210. [Abstract] [Full Text] [PDF]
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L. Guizani-Tabbane, K. Ben-Aissa, M. Belghith, A. Sassi, and K. Dellagi Leishmania major Amastigotes Induce p50/c-Rel NF-{kappa}B Transcription Factor in Human Macrophages: Involvement in Cytokine Synthesis Infect. Immun., May 1, 2004; 72(5): 2582 - 2589. [Abstract] [Full Text] [PDF]
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P. Kropf, M. A. Freudenberg, M. Modolell, H. P. Price, S. Herath, S. Antoniazi, C. Galanos, D. F. Smith, and I. Muller Toll-Like Receptor 4 Contributes to Efficient Control of Infection with the Protozoan Parasite Leishmania major Infect. Immun., April 1, 2004; 72(4): 1920 - 1928. [Abstract] [Full Text] [PDF]
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N. B. Norsworthy, J. Sun, D. Elnaiem, G. Lanzaro, and L. Soong Sand Fly Saliva Enhances Leishmania amazonensis Infection by Modulating Interleukin-10 Production Infect. Immun., March 1, 2004; 72(3): 1240 - 1247. [Abstract] [Full Text] [PDF]
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M. Hesse, C. A. Piccirillo, Y. Belkaid, J. Prufer, M. Mentink-Kane, M. Leusink, A. W. Cheever, E. M. Shevach, and T. A. Wynn The Pathogenesis of Schistosomiasis Is Controlled by Cooperating IL-10-Producing Innate Effector and Regulatory T Cells J. Immunol., March 1, 2004; 172(5): 3157 - 3166. [Abstract] [Full Text] [PDF]
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H. Qi, J. Ji, N. Wanasen, and L. Soong Enhanced Replication of Leishmania amazonensis Amastigotes in Gamma Interferon-Stimulated Murine Macrophages: Implications for the Pathogenesis of Cutaneous Leishmaniasis Infect. Immun., February 1, 2004; 72(2): 988 - 995. [Abstract] [Full Text] [PDF]
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R. C. Huard, S. Chitale, M. Leung, L. C. O. Lazzarini, H. Zhu, E. Shashkina, S. Laal, M. B. Conde, A. L. Kritski, J. T. Belisle, et al. The Mycobacterium tuberculosis Complex-Restricted Gene cfp32 Encodes an Expressed Protein That Is Detectable in Tuberculosis Patients and Is Positively Correlated with Pulmonary Interleukin-10 Infect. Immun., December 1, 2003; 71(12): 6871 - 6883. [Abstract] [Full Text] [PDF]
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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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U. M. Padigel, J. Alexander, and J. P. Farrell The Role of Interleukin-10 in Susceptibility of BALB/c Mice to Infection with Leishmania mexicana and Leishmania amazonensis J. Immunol., October 1, 2003; 171(7): 3705 - 3710. [Abstract] [Full Text] [PDF]
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J. Ji, J. Sun, and L. Soong Impaired Expression of Inflammatory Cytokines and Chemokines at Early Stages of Infection with Leishmania amazonensis Infect. Immun., August 1, 2003; 71(8): 4278 - 4288. [Abstract] [Full Text] [PDF]
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 D. R. Jeyarajah, M. L. Kielar, N. Frantz, G. Lindberg, and C. Y. Lu Infection by Gram-Negative Organisms via the Biliary Route Results in Greater Mortality than Portal Venous Infection Clin. Vaccine Immunol., July 1, 2003; 10(4): 664 - 669. [Abstract] [Full Text] [PDF]
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M. Colmenares, P. E. Kima, E. Samoff, L. Soong, and D. McMahon-Pratt Perforin and Gamma Interferon Are Critical CD8+ T-Cell-Mediated Responses in Vaccine-Induced Immunity against Leishmania amazonensis Infection Infect. Immun., June 1, 2003; 71(6): 3172 - 3182. [Abstract] [Full Text] [PDF]
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N. Noben-Trauth, R. Lira, H. Nagase, W. E. Paul, and D. L. Sacks The Relative Contribution of IL-4 Receptor Signaling and IL-10 to Susceptibility to Leishmania major J. Immunol., May 15, 2003; 170(10): 5152 - 5158. [Abstract] [Full Text] [PDF]
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D. V. R. Bullen, T. M. Baldwin, J. M. Curtis, W. S. Alexander, and E. Handman Persistence of Lesions in Suppressor of Cytokine Signaling-1-Deficient Mice Infected with Leishmania major J. Immunol., April 15, 2003; 170(8): 4267 - 4272. [Abstract] [Full Text] [PDF]
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S. Ahmed, M. Colmenares, L. Soong, K. Goldsmith-Pestana, L. Munstermann, R. Molina, and D. McMahon-Pratt Intradermal Infection Model for Pathogenesis and Vaccine Studies of Murine Visceral Leishmaniasis Infect. Immun., January 1, 2003; 71(1): 401 - 410. [Abstract] [Full Text] [PDF]
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M. Colmenares, S. L. Constant, P. E. Kima, and D. McMahon-Pratt Leishmania pifanoi Pathogenesis: Selective Lack of a Local Cutaneous Response in the Absence of Circulating Antibody Infect. Immun., December 1, 2002; 70(12): 6597 - 6605. [Abstract] [Full Text] [PDF]
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H. W. Murray, C. M. Lu, S. Mauze, S. Freeman, A. L. Moreira, G. Kaplan, and R. L. Coffman Interleukin-10 (IL-10) in Experimental Visceral Leishmaniasis and IL-10 Receptor Blockade as Immunotherapy Infect. Immun., November 1, 2002; 70(11): 6284 - 6293. [Abstract] [Full Text] [PDF]
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J. Li, U. M. Padigel, P. Scott, and J. P. Farrell Combined Treatment with Interleukin-12 and Indomethacin Promotes Increased Resistance in BALB/c Mice with Established Leishmania major Infections Infect. Immun., October 1, 2002; 70(10): 5715 - 5720. [Abstract] [Full Text] [PDF]
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 J. C. Delorenzi, L. Freire-de-Lima, C. R. Gattass, D. de Andrade Costa, L. He, M. E. Kuehne, and E. M. B. Saraiva In Vitro Activities of Iboga Alkaloid Congeners Coronaridine and 18-Methoxycoronaridine against Leishmania amazonensis Antimicrob. Agents Chemother., July 1, 2002; 46(7): 2111 - 2115. [Abstract] [Full Text] [PDF]
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P. Launois, A. Gumy, H. Himmelrich, R. M. Locksley, M. Rocken, and J. A. Louis Rapid IL-4 Production by Leishmania Homolog of Mammalian RACK1-Reactive CD4+ T Cells in Resistant Mice Treated Once with Anti-IL-12 or -IFN-{gamma} Antibodies at the Onset of Infection with Leishmania major Instructs Th2 Cell Development, Resulting in Nonhealing Lesions J. Immunol., May 1, 2002; 168(9): 4628 - 4635. [Abstract] [Full Text] [PDF]
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D. E. Jones, M. R. Ackermann, U. Wille, C. A. Hunter, and P. Scott Early Enhanced Th1 Response after Leishmania amazonensis Infection of C57BL/6 Interleukin-10-Deficient Mice Does Not Lead to Resolution of Infection Infect. Immun., April 1, 2002; 70(4): 2151 - 2158. [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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B. Hondowicz and P. Scott Influence of Parasite Load on the Ability of Type 1 T Cells To Control Leishmania major Infection Infect. Immun., February 1, 2002; 70(2): 498 - 503. [Abstract] [Full Text] [PDF]
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A. Sing, A. Roggenkamp, A. M. Geiger, and J. Heesemann Yersiniaenterocolitica Evasion of the Host Innate Immune Response by V Antigen-Induced IL-10 Production of Macrophages Is Abrogated in IL-10-Deficient Mice J. Immunol., February 1, 2002; 168(3): 1315 - 1321. [Abstract] [Full Text] [PDF]
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G. Trinchieri Regulatory Role of T Cells Producing both Interferon {gamma} and Interleukin 10 in Persistent Infection J. Exp. Med., November 19, 2001; 194(10): F53 - F57. [Full Text] [PDF]
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Y. Belkaid, K. F. Hoffmann, S. Mendez, S. Kamhawi, M. C. Udey, T. A. Wynn, and D. L. Sacks The Role of Interleukin (IL)-10 in the Persistence of Leishmania major in the Skin after Healing and the Therapeutic Potential of Anti-IL-10 Receptor Antibody for Sterile Cure J. Exp. Med., November 19, 2001; 194(10): 1497 - 1506. [Abstract] [Full Text] [PDF]
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0.05) at day 21 and beyond. *,
Wild-type mice were euthanized at day 36 of the experiment for
humane reasons. B, Footpad parasite burdens
(log10) were measured by limiting dilution analysis at 14
days postinfection (n = 5/group)
(left), and, in a separate experiment, on day 36
(n = 5) and day 77 (n = 3)
postinfection (right). Wild-type BALB/c mice (gray bars)
and IL-10-/- mice (filled bars). Double asterisks
represent a difference of p 
