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Are Overcome to Control Infection with Leishmania donovani in CC Chemokine Receptor (CCR) 5-, Macrophage Inflammatory Protein-1
-, or CCR2-Deficient Mice1
*
South Texas Veterans Health Care System, Audie L. Murphy Division, Departments of
Medicine and
Pathology, University of Texas Health Science Center, San Antonio, TX 78229;
§
Section of Molecular Genetics and Microbiology and
¶
Institute of Cellular and Molecular Biology, University of Texas, Austin, TX 78712; and
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Department of Pathology and Laboratory Medicine, University of North Carolina Medical School, Chapel Hill, NC 27599
 |
Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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(MIP-1), a ligand for CCR5, in
two situations: following T cell stimulation or after challenge with
Leishmania donovani, an intracellular microbe whose
control is dependent on a Th1 immune response. Mice deficient in CCR5,
MIP-1, or CCR2 had reduced IFN-
responses following ligation of
the TCR. Reduced IFN- responses following PMA and ionomycin were
also observed in CD8+ T cells of CCR5-/- and
CCR2-/- mice. During the early phases of infection, all
three knockout mice had low Ag-specific IFN- responses. However,
this reduced IFN- response was overcome during a state of persistent
Ag stimulation (chronic infection), and was not associated with an
adverse parasitologic outcome in any of the gene-targeted mouse
strains. To the contrary, during the late phase of infection, an
exaggerated Ag-specific IFN- response was evident in
CCR5-/- and MIP-1-/- mice, and this
correlated with an enhanced control of parasite replication. Although
granuloma formation was abnormal in each of the knockout mice, there
was no correlation between the number or architecture of the granulomas
and parasite burden. Collectively, these findings indicate
an important role for CCR5, MIP-1, and CCR2 in granulomatous
inflammation, and that CCR5 and MIP-1, possibly acting through CCR5,
might play a deleterious role in the outcome of chronic L.
donovani infection. Our data also suggest that there might be
cross-talk between TCR and chemokine receptor signaling
pathways. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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3 is a ligand
for CCR1, CCR5, and CCR9, and MCP-1, -2, -3, -4, and -5 are the ligands
for CCR2.
Mice with targeted deletions of chemokines and/or their receptors will
be helpful in elucidating the functional relevance of this complex
ligand-receptor promiscuity as well as in clarifying further the recent
observation that these molecules may play a role in Th1-Th2 (e.g.,
IFN- in Th1 and IL-4 in Th2 responses)-mediated immune responses
(10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23). Th1- or IFN--mediated responses are important
for the control of intracellular infections, whereas Th2 responses are
more effective for the control of extracellular infections.
In this paper we have focused our study on mice deficient in the
following molecules: MIP-1; CCR5, a receptor for MIP-1, MIP-1ß,
and RANTES (24, 25, 26); and CCR2 (27, 28). On an
ICR genetic background, mice deficient in CCR5
(CCR5-/-) had impaired macrophage function and
enhanced T cell dependent immune response (29). There are
several studies that have used mice deficient in MIP-1 to explore
its role in viral infection (30, 31, 32); however, few studies
have addressed its function in nonviral infections. With regard to
mice deficient in CCR2, we have demonstrated recently that
CCR2-deficient mice have a severe reduction in leukocyte adhesion and
monocyte extravasation (33). Boring et al. have shown that
CCR2-/- mice have impaired Th1 cytokine
responses to lung granulomas induced by Mycobacterium bovis
purified protein derivative (PPD) (34), and in a separate
study CCR2-/- mice were unable to clear
effectively Listeria monocytogenes infection
(35).
We postulated that the concurrent analyses of the immune and host
defense functions in mice deficient in CCR5, MIP-1, or CCR2 would
provide insights into the functional redundancy, if any, of these
molecules in vivo. For example, the concurrent analyses of mice
deficient in CCR5 or MIP-1 would allow for an improved understanding
of the role of the MIP-1-CCR5 vs the MIP-1-CCR1 or MIP-1-CCR9
ligand-receptor axis in host defenses. To this end, we investigated the
Th1 responses in mice deficient in CCR5, MIP-1, or CCR2 and
correlated these responses to their ability to control infection by the
intracellular parasite L. donovani.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CCR2-/- and
MIP-1-/- mice were described previously by
Kuziel et al. (33) and Cook et al. (32),
respectively. The CCR5-/- mice were generated
by deletion of the entire coding region of the CCR5 gene
(W. A. Kuziel, T .C. Dawson, R. L. Reddick, and N. Maeda,
manuscript in preparation). Wild-type (+/+),
CCR5-/-, MIP-1-/-,
and CCR2-/- mice were on an outbred
C57BL/6J x 129/Ola genetic background (n 
6
generations). Mice were born and bred under specific pathogen-free
conditions. At 5–6 wk of age, mice were transferred from the
University of Texas (Austin, TX) to the University of Texas Health
Science Center (San Antonio, TX). In this paper, mice with targeted
gene deletions are also referred as knockout (KO) mice. All protocols
were approved by the respective institutional animal care and use
committee. L. donovani 1S strain (MHOM/SD/001S-2D)
promastigotes were cultured, and soluble L. donovani Ag
(SLDA) was prepared as described previously (36). Mice
were infected by the i.v. route (lateral tail vein) with 1 x
107 stationary phase promastigotes in 100 µl of
PBS. The parasite burden was quantified in spleen and liver by the
limiting dilution culture method as described previously (37, 38).
Cell culture and cytokine analysis
For studies that determined the responses of spleen cells
following anti-CD3 mAb and anti-CD28 mAb stimulation, 24-well
plates were coated (overnight at 4°C) with 10 µg/ml of anti-rat
IgG (KPL, Gaithersburg, MD) in 50 mM
NaHCO3-Na2CO3
(pH 9.6) and then washed with RPMI 1640 three times. One milliliter of
2.5 or 5 x 106 cells/ml of spleen cells
were cultured in RPMI 1640 containing 10% FCS with 0.3 µg/ml of rat
anti-mouse CD3 mAb (Serotec, Raleigh, NC) and 1 µg/ml of hamster
anti-mouse CD28 mAb (PharMingen, San Diego, CA). After 48 h
supernatants were harvested, and ELISA was used to determine IFN-
levels in the culture supernatants.
For Ag-specific cytokine production, 1 ml of 5 x
106 cells/ml spleen cells were cultured with or
without 50 µg/ml of SLDA in 24-well plates. After 24 h,
supernatants were harvested, and ELISA was used to determine the
cytokine levels. In blocking experiments, 200 µl of 5 x
105 spleen cells were cultured in 96-well plates.
Anti-CD4 mAb, anti-CD8 mAb, purified rat IgG2b (isotype control for
anti-CD4 mAb), purified rat IgG2a (isotype control for anti-CD8
mAb), or cyclosporin A (Sigma, St. Louis, MO) was added before adding
50 µg/ml of SLDA. After 48 h, supernatants were harvested, and
ELISA was used to determine IFN- levels.
For ELISA we used paired mAbs and recombinant murine IFN-, IL-2,
IL-4, and IL-12 (PharMingen). Ninety-six-well microtiter plates
(Maxisorb, Nunc, Naperville, IL) were coated overnight at 4°C with 50
µl/well of anti-cytokine capture Ab (2 µg/ml in 50 mM
NaHCO3-Na2CO3,
pH 9.6) and then washed with PBS containing 0.05% Tween-20 (wash
buffer). Nonspecific binding was blocked by coating the microtiter
plate with 1% BSA-PBS for 30 min at room temperature. Standard or
samples (100 µl/well) were added to the microtiter plates, incubated
overnight at 4°C, washed four times, and then incubated with
biotinylated Ab (100 µl/well; 1 µg/ml of Ab in PBS containing
0.05% Tween-20 and 1% BSA) for 1 h at room temperature. Plates
were washed six times, and streptavidin-alkaline phosphatase
(PharMingen) was added for 30 min at room temperature. Plates were
then washed eight times, and p-nitrophenyl phosphate
disodium salt tablet (PNPP) (Pierce, Rockford, IL) dissolved in 10 mM
diethanolamine buffer (pH 9.5) was added for color development (at room
temperature), and OD was determined by a plate reader. The murine IL-10
ELISA kit (Quankine M Immunoassay) was purchased from R & D Systems
(Minneapolis, MN). The upper and lower limits of detection for ELISA
were 15.6–1000 pg/ml for IFN-, 7.8–500 pg/ml for IL-2, 15.6–1000
pg/ml for IL-4, and 12.3–9000 pg/ml for IL-12.
Flow cytometric analysis of intracellular IFN-
Cytofix/Cytoperm Plus (with GolgiStop) Kit, Fc Block
(anti-CD16/CD32), FITC-labeled rat IgG1 mAb, FITC-labeled
anti-IFN- mAb, unlabeled anti-IFN- mAb, PE-labeled
anti-CD4 mAb, and PE-labeled anti-CD8 mAb were from PharMingen.
Spleen cells were resuspended at 2 x 106/ml
and stimulated with 25 ng/ml PMA and 1 µg/ml ionomycin for 14 h.
Golgistop was added during the last 4 h of cell stimulation. Cells
were washed and incubated with Fc Block for 15 min at 4°C, washed,
and then stained with PE-labeled anti-CD4 mAb or PE-labeled
anti-CD8 mAb for 15 min at 4°C. Cells were washed again, fixed
with Cytofix/Cytoperm solution for 20 min at 4°C, washed twice with
1x Perm/Wash solution, and stained with FITC-labeled rat IgG1 (isotype
control) or FITC-labeled anti-IFN- mAb for 30 min at 4°C. For
cold inhibition, cells were incubated with 10 µg of unlabeled
anti-IFN- mAb for 30 min before staining. Cells were washed
twice and fixed with PBS containing 1% paraformaldehyde and 5 mM EDTA
in PBS, the staining was determined by FACSCalibur (Becton Dickinson,
San Jose, CA), and the data were analyzed by CellQuest software. The
wash solution was 0.5% BSA in PBS unless otherwise indicated.
Histopathology
The distribution and cellular composition of inflammatory cell infiltrates were examined in slides of paraffin-embedded livers stained with hematoxylin and eosin. The pathologist (R.L.R.) reviewing the histopathologic slides was blinded to the identity of the source of the tissue sections.
Statistical analysis
Results are expressed as the mean ± SD. Group comparisons were made by ANOVA or Kruskal-Wallis, followed by Dunnett’s test to determine differences between wild-type and KO mice.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production by uninfected CCR5-, MIP-1-, and
CCR2-deficient mice
The production of IFN- by spleen T cells obtained from
uninfected mice deficient in CCR5, MIP-1, and CCR2 was determined in
vitro following stimulation of the TCR and CD28 (Fig. 1
) or after activation by PMA and
ionomycin (Fig. 2, A–D). In
multiple experiments at cell concentrations of either 5 (Fig. 1A) or 2.5 (Fig. 1B) x
106 cells/ml, the amount of IFN- produced by
spleen cells following ligation of the TCR with anti-CD3 mAb and
anti-CD28 mAb was significantly lower in mice deficient in
CCR5, MIP-1, or CCR2. We were unable to detect IL-4 in the
supernatants of spleen cells stimulated with anti-CD3 mAb and
anti-CD28 mAb.
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was similar in
the KO and control mice (Fig. 2
, A and B). In
contrast, compared with wild-type mice, the percentage of spleen
CD8+ T cells that stained positive for IFN-
was significantly lower in CCR5-/- and
CCR2-/- mice (Fig. 2, C and
D). In MIP-1-/- mice the
percentage of spleen CD8+ T cells that stained
positive for IFN- was comparable to that in wild-type mice (Fig. 2, C and D). These results were concordant with the
finding that following stimulation with PMA and ionomycin, the amount
of IFN- produced by purified CD8+ T cells
was lower in CCR5-/- (71 ng/ml) and
CCR2-/- (105 ng/ml) mice compared with that in
wild-type mice (146 ng/ml).
Course of L. donovani infection in CCR5-, MIP-1-,
and CCR2-deficient mice
Since under certain in vitro experimental conditions,
the amount of IFN- produced by CCR5-, MIP-1-, or CCR2-deficient
mice was reduced, we determined whether this influenced the course of
infection by the intracellular parasite, L. donovani. The
murine model of visceral leishmaniasis has been well characterized, and
control of L. donovani in this model is known to be
dependent on Th1 (IFN-) cell responses (37, 39, 40).
The KO and wild-type mice were infected with L. donovani
i.v., and the extent of infection was determined 4 days, 4 wk, and 8 wk
postinfection. At all time points, the parasite burden in the spleen
and liver of CCR2-/- mice was similar to that
in wild-type mice (Fig. 3, A
and B). In contrast, the parasite burden in the spleen and
liver of CCR5-/- and
MIP-1-/- mice showed less of an increase
over time, and 8 wk postinfection, the parasite burden in the liver was
significantly lower (
4 log) in CCR5-/-
and MIP-1-/- mice than in wild-type
mice. These findings demonstrated that CCR5, MIP-1, and CCR2 were
not essential for containment of murine L. donovani
infection.
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-, and CCR2-deficient mice
infected with L. donovani
Four days postinfection the Ag-specific IFN- production by
spleen cells of CCR5-/-,
MIP-1-/-, or CCR2-/-
mice was significantly lower than in wild-type mice (Fig. 4A). Four weeks postinfection,
Ag-specific IFN- production by spleen cells was similar in all mouse
groups, as were the parasite burdens (Figs. 3 and 4A).
However, at 8 wk postinfection, the Ag-specific IFN- production was
significantly higher in spleen cells derived from infected
CCR5-/- or MIP-1-/-
mice compared with wild-type or CCR2-/- mice
(Fig. 4A). In general, the Ag-specific IL-2 production
in spleen cells of infected KO mice mirrored the Ag-specific production
of IFN- (Fig. 4, A and B). The only exception
was in CCR2-/- mice, where at 4 days
postinfection the IL-2 values were similar to those in wild-type mice
(Fig. 4B). The Ag-specific IL-10 production was similar in
all mice groups (Fig. 4C), whereas IL-4 and IL-12 were not
detected in the spleen cell supernatants from the different mouse
groups (data not shown).
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production, we conducted blocking experiments using
anti-CD4 mAb and anti-CD8 mAb. Anti-CD4 mAb completely
inhibited IFN- production from spleen cells obtained
from 8-wk-infected mice (Fig. 5,
A–D). In contrast, anti-CD8 mAb did not abrogate the
production of Ag-specific IFN- from spleen cells. The
Ag-specific IFN- production by spleen cells was inhibited
completely by cyclosporin A (Fig. 5E). This observation
in conjunction with the finding that anti-CD4 mAb inhibited IFN-
production indicates that CD4+ lymphocytes, and
not NK cells, are likely to be the main source of IFN- in 8-wk
L. donovani-infected mice, since cyclosporin A does not
inhibit IFN- production from NK cells stimulated with IL-2 and IL-12
(41).
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produced by CD8+ T cells derived from uninfected
CCR5-/- and CCR2-/-
mice was lower than that in wild-type mice (Fig. 2, C and
D). We therefore examined whether this defect persisted
during the course of infection. At 4 days, and 4- and 8-wk
postinfection, the percentage of spleen CD8+ T
cells that stained positive for IFN- remained lower in
CCR5-/- and CCR2-/-
mice (Fig. 2E).
Role of CCR5, MIP-1, and CCR2 in granulomatous
inflammation
Mice deficient in molecules important for the recruitment and
activation of leukocytes might have concurrent defects in granuloma
formation. We therefore studied the evolution of the granulomatous
inflammatory response during different phases of L. donovani
infection in mice deficient in CCR5, MIP-1, or CCR2 (Figs. 6 and 7).
Differences in the granulomatous inflammatory response to infection
were visible in the KO mice as early as 4 days postinfection. At this
early time point, compact aggregates of Kupffer cells were evident in
the hepatic parenchyma of wild-type mice (data not shown). In contrast,
in all KO mice, the Kupffer cell aggregates were not well organized,
and in CCR2-/- and
MIP-1-/- mice the size of the Kupffer cell
aggregates was significantly smaller than that in wild-type mice (Fig. 6A).
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A). Although we could not estimate the exact diameter of
the granulomas in CCR5-/- mice, the collection
of inflammatory cells was larger than in
CCR2-/- or MIP-1-/-
mice and was more comparable to that seen in wild-type mice. At this
time point, the number of granulomas in
MIP-1-/- and CCR2-/-
mice was significantly lower than that in wild-type mice (Fig. 6B).
Eight weeks postinfection, wild-type mice had large, well-organized
granulomas dispersed throughout the hepatic parenchyma (Fig. 7A). Well-organized as well as poorly organized granulomas
were found in MIP-1-/- (Fig. 7C)
and CCR2-/- (Fig. 7D) mice; however,
in CCR5-/- mice, well-organized granulomas were
rarely found (Fig. 7B). At this time point postinfection,
the KO mice tended to have lower numbers of granulomas, and this
finding was especially prominent in MIP-1-deficient mice (Fig. 6B).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, and CCR2 influence the
production of IFN- by T cells following 1) stimulation of the TCR
and CD28 by anti-CD3 and anti-CD28 mAbs (Fig. 1), 2) activation
of protein kinase C and calcium mobilization directly by PMA and
ionomycin (Fig. 2), and 3) Ag-specific stimulation (Fig. 4). Reduced
IFN- production was seen after TCR ligation in the three KO mice
studied (Fig. 1). However, when TCR was bypassed with PMA and
ionomycin, reduced IFN- responses were evident only in
CD8+ T cells from CCR5-/-
and CCR2-/- mice (Fig. 2, C and
D). These findings suggest that the IFN- responses in
these KO mice are complex and highly dependent on the nature of the
stimulation used. These data also suggest that there might be
cross-talk between TCR and chemokine receptor signaling pathways.
In agreement with Boring et al. (34), we found that CCR2
may play an important role in IFN- production. These investigators
showed that following noninfectious granulomatous inflammation induced
by i.v. administration of Sephadex beads coated with PPD from
Mycobacterium bovis into PPD-sensitized mice, mice lacking
CCR2 exhibited an impaired IFN- response.
CCR2-/- spleen cells stimulated by Con A
produced lower amounts of IFN- than wild-type spleen cells; however,
IL-2 levels were not reduced (34). We confirm and extend
these findings by demonstrating that naive
CCR2-/- spleen cells stimulated via CD3/TCR
produced lower amounts of IFN- than those from wild-type mice (Fig. 1) and show that following stimulation with PMA/ionomycin,
CD8+ T cells from uninfected (Fig. 2, C and D) or infected (Fig. 2E)
CCR2-/- mice produce lower amounts of
IFN-.
The Ag-specific IFN- response in wild-type mice did not change
during the course of infection (Fig. 4A). However, in CCR5
and MIP-1 KO mice this response shifted from a low to an exaggerated
response, while in CCR2-/- mice the Ag-specific
IFN- response shifted from a low response to a response similar to
that in wild-type mice. In fact, 8 wk following infection, the
magnitude of the Ag-specific IFN- and IL-2 responses was directly
proportional to the clearance of L. donovani infection
(lower parasite burden). The mechanisms responsible for this shift in
Ag-specific IFN- responses during the course of infection in these
KO mice is not clear. Nevertheless, our studies with mAb blocking
studies suggest that the cell type responsible for the exaggerated
Ag-specific IFN- response in CCR5-/- and
MIP-1-/- mice is likely to be
CD4+ T cells (Fig. 5).
Deficiency in CCR5, MIP-1, or CCR2 was not associated with an
adverse consequence with regard to control of intracellular infection
with L. donovani (Fig. 3). CCR2-/-
mice could adequately contain infection, whereas mice deficient in CCR5
and MIP-1 had a lower parasite burden. These findings suggest that
CCR5 and MIP-1 (possible acting via CCR5) might play a deleterious
role in the outcome of chronic L. donovani infection (Fig. 3B). One of the advantages of concurrently analyzing several
KO mouse strains and a control strain, all of which are on a similar
outbred genetic background (B6 x 129), is that genetic influences
on the results observed might be more apparent. The fact that we saw
resistance to L. donovani only in two of the four strains
examined suggests strongly that the resistance is due to the deletion
of CCR5 or MIP-1 and not to the genetic background. Genetic
background may well influence or modulate a result to some degree. For
example, Zhou et al. recently reported that
CCR5-/- mice had enhanced T cell-mediated
immune responses (29). We observed an enhanced T
cell-mediated immune response only in spleen cells of 8-wk-infected
CCR5-/- mice. The basis for the discrepancy
between our findings and those of Zhou et al. is not clear, but may
reflect differences in the strains used to generate CCR5-deficient mice
(ICR vs C57BL/6J in this study).
Given the important role of chemokines and their receptors in leukocyte
trafficking it was not surprising that the KO mice studied had marked
abnormalities in granuloma formation (Figs. 6 and 7). An impairment in
granuloma formation has also been observed in mice deficient in CCR1
(42), and our studies confirm the findings of Kuziel et
al. (33) and Boring et al. (34), who also
demonstrated that CCR2-deficient mice had reduced granuloma sizes. In
this study we found no correlation between size or architecture (poor
vs well organized) of the granuloma and eventual outcome. Furthermore,
despite the concordance in the IFN- response and the course of
infection in CCR5-/- and
MIP-1-/- mice, a discordant pattern was
observed in their granulomatous response to L. donovani
infection. A more detailed analysis of the cells recruited to the
granuloma might shed additional light on the roles of CCR5, MIP-1,
and CCR2 in granulomatous inflammation.
The ability of CCR5 mice to contain L. donovani infection is
in contrast to their marked susceptibility to Cryptococcal
neoformans infection (43). The immunological and host
defense phenotype of MIP-1-/- mice has been
examined mostly in the setting of viral infections
(30, 31, 32). Cook et al. observed that MIP-1 null mice
were resistant to coxsackievirus-induced myocarditis and had
reduced lung inflammation following influenza infection
(32). In a murine model of herpes simplex virus type 1
infection, Tumpey et al. demonstrated recently that compared with
wild-type mice, MIP-1 null mice had markedly reduced corneal
opacity, a prominent reduction in T cell and neutrophil migration, and
lower levels of the Th1 cytokines IL-2 and IFN- (31).
However, virus replication and clearance were similar in both the
MIP-1 gene-deleted and control mice (31). Our finding
suggests that the immune response observed in
CCR5-/-, MIP-1-/-,
or CCR2-/- mice is likely to be highly
dependent on the nature of the in vitro (e.g., anti-CD3 mAb and
anti-CD28 mAb vs PMA/ionomycin stimulation) and in vivo (microbe
used for challenge) experimental conditions employed to dissect the
immunological phenotype of these mice. Nevertheless, our studies
demonstrate an important role for CCR5, MIP-1, and CCR2 in the
generation of IFN- by T cells and indicate that they collectively
participate in the host defense against intracellular pathogens such as
L. donovani.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Seema S. Ahuja, Department of Medicine, 7703 Floyd Curl Drive, University of Texas Health Science Center, San Antonio, TX 78229-3900. E-mail address:
3 Abbreviations used in this paper: MIP, macrophage inflammatory protein; MCP, monocyte chemoattractant protein; SLDA, soluble Leishmania donovani Ag; KO, knockout; PPD, purified-protein derivative.
Received for publication June 21, 1999. Accepted for publication August 27, 1999.
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), MIP-1(ß), and RANTES. J. Leukocyte Biol. 60:147.[Abstract]
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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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P. K. Henke, C. G. Pearce, D. M. Moaveni, A. J. Moore, E. M. Lynch, C. Longo, M. Varma, N. A. Dewyer, K. B. Deatrick, G. R. Upchurch Jr, et al. Targeted Deletion of CCR2 Impairs Deep Vein Thombosis Resolution in a Mouse Model. J. Immunol., September 1, 2006; 177(5): 3388 - 3397. [Abstract] [Full Text] [PDF]
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R. Palaniappan, S. Singh, U. P. Singh, R. Singh, E. W. Ades, D. E. Briles, S. K. Hollingshead, W. Royal III, J. S. Sampson, J. K. Stiles, et al. CCL5 Modulates Pneumococcal Immunity and Carriage J. Immunol., February 15, 2006; 176(4): 2346 - 2356. [Abstract] [Full Text] [PDF]
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J. L. Hardison, R. A. Wrightsman, P. M. Carpenter, W. A. Kuziel, T. E. Lane, and J. E. Manning The CC Chemokine Receptor 5 Is Important in Control of Parasite Replication and Acute Cardiac Inflammation following Infection with Trypanosoma cruzi Infect. Immun., January 1, 2006; 74(1): 135 - 143. [Abstract] [Full Text] [PDF]
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C. A. Wysocki, Q. Jiang, A. Panoskaltsis-Mortari, P. A. Taylor, K. P. McKinnon, L. Su, B. R. Blazar, and J. S. Serody Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease Blood, November 1, 2005; 106(9): 3300 - 3307. [Abstract] [Full Text] [PDF]
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 C Goulding, A Murphy, G MacDonald, S Barrett, J Crowe, J Hegarty, S McKiernan, and D Kelleher The CCR5-{Delta}32 mutation: impact on disease outcome in individuals with hepatitis C infection from a single source Gut, August 1, 2005; 54(8): 1157 - 1161. [Abstract] [Full Text] [PDF]
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P. M. Robben, M. LaRegina, W. A. Kuziel, and L. D. Sibley Recruitment of Gr-1+ monocytes is essential for control of acute toxoplasmosis J. Exp. Med., June 6, 2005; 201(11): 1761 - 1769. [Abstract] [Full Text] [PDF]
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K. L. Hokeness, W. A. Kuziel, C. A. Biron, and T. P. Salazar-Mather Monocyte Chemoattractant Protein-1 and CCR2 Interactions Are Required for IFN-{alpha}/{beta}-Induced Inflammatory Responses and Antiviral Defense in Liver J. Immunol., February 1, 2005; 174(3): 1549 - 1556. [Abstract] [Full Text] [PDF]
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 A. HAILU, T. VAN DER POLL, N. BERHE, and P. A. KAGER ELEVATED PLASMA LEVELS OF INTERFERON (IFN)-{gamma}, IFN-{gamma} INDUCING CYTOKINES, AND IFN-{gamma} INDUCIBLE CXC CHEMOKINES IN VISCERAL LEISHMANIASIS Am J Trop Med Hyg, November 1, 2004; 71(5): 561 - 567. [Abstract] [Full Text] [PDF]
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B.-C. Chiu, C. M. Freeman, V. R. Stolberg, J. S. Hu, K. Zeibecoglou, B. Lu, C. Gerard, I. F. Charo, S. A. Lira, and S. W. Chensue Impaired Lung Dendritic Cell Activation in CCR2 Knockout Mice Am. J. Pathol., October 1, 2004; 165(4): 1199 - 1209. [Abstract] [Full Text] [PDF]
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H. M. Scott Algood and J. L. Flynn CCR5-Deficient Mice Control Mycobacterium tuberculosis Infection despite Increased Pulmonary Lymphocytic Infiltration J. Immunol., September 1, 2004; 173(5): 3287 - 3296. [Abstract] [Full Text] [PDF]
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C. A. Wysocki, S. B. Burkett, A. Panoskaltsis-Mortari, S. L. Kirby, A. D. Luster, K. McKinnon, B. R. Blazar, and J. S. Serody Differential Roles for CCR5 Expression on Donor T Cells during Graft-versus-Host Disease Based on Pretransplant Conditioning J. Immunol., July 15, 2004; 173(2): 845 - 854. [Abstract] [Full Text] [PDF]
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R. W. DePaolo, R. Lathan, and W. J. Karpus CCR5 Regulates High Dose Oral Tolerance by Modulating CC Chemokine Ligand 2 Levels in the GALT J. Immunol., July 1, 2004; 173(1): 314 - 320. [Abstract] [Full Text] [PDF]
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 A. D. Schecter, A. B. Berman, L. Yi, H. Ma, C. M. Daly, K. Soejima, B. J. Rollins, I. F. Charo, and M. B. Taubman MCP-1-dependent signaling in CCR2-/- aortic smooth muscle cells J. Leukoc. Biol., June 1, 2004; 75(6): 1079 - 1085. [Abstract] [Full Text] [PDF]
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M. X. Zhong, W. A. Kuziel, E. G. Pamer, and N. V. Serbina Chemokine Receptor 5 Is Dispensable for Innate and Adaptive Immune Responses to Listeria monocytogenes Infection Infect. Immun., February 1, 2004; 72(2): 1057 - 1064. [Abstract] [Full Text] [PDF]
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I. Szabo, M. A. Wetzel, N. Zhang, A. D. Steele, D. E. Kaminsky, C. Chen, L.-Y. Liu-Chen, F. Bednar, E. E. Henderson, O. M. Z. Howard, et al. Selective inactivation of CCR5 and decreased infectivity of R5 HIV-1 strains mediated by opioid-induced heterologous desensitization J. Leukoc. Biol., December 1, 2003; 74(6): 1074 - 1082. [Abstract] [Full Text]
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 P. Spagnolo, E. A. Renzoni, A. U. Wells, H. Sato, J. C. Grutters, P. Sestini, A. Abdallah, E. Gramiccioni, H. J. T. Ruven, R. M. du Bois, et al. C-C Chemokine Receptor 2 and Sarcoidosis: Association with Lofgren's Syndrome Am. J. Respir. Crit. Care Med., November 15, 2003; 168(10): 1162 - 1166. [Abstract] [Full Text] [PDF]
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A. R. Rao, M. P. Quinones, E. Garavito, Y. Kalkonde, F. Jimenez, C. Gibbons, J. Perez, P. Melby, W. Kuziel, R. L. Reddick, et al. CC Chemokine Receptor 2 Expression in Donor Cells Serves an Essential Role in Graft-versus-Host-Disease J. Immunol., November 1, 2003; 171(9): 4875 - 4885. [Abstract] [Full Text] [PDF]
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R. W. DePaolo, B. J. Rollins, W. Kuziel, and W. J. Karpus CC Chemokine Ligand 2 and Its Receptor Regulate Mucosal Production of IL-12 and TGF-{beta} in High Dose Oral Tolerance J. Immunol., October 1, 2003; 171(7): 3560 - 3567. [Abstract] [Full Text] [PDF]
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 X. Huang and L. D. Hazlett Analysis of Pseudomonas aeruginosa Corneal Infection Using an Oligonucleotide Microarray Invest. Ophthalmol. Vis. Sci., August 1, 2003; 44(8): 3409 - 3416. [Abstract] [Full Text] [PDF]
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C. R. Brown, V. A. Blaho, and C. M. Loiacono Susceptibility to Experimental Lyme Arthritis Correlates with KC and Monocyte Chemoattractant Protein-1 Production in Joints and Requires Neutrophil Recruitment Via CXCR2 J. Immunol., July 15, 2003; 171(2): 893 - 901. [Abstract] [Full Text] [PDF]
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E. Belnoue, F. T. M. Costa, A. M. Vigario, T. Voza, F. Gonnet, I. Landau, N. van Rooijen, M. Mack, W. A. Kuziel, and L. Renia Chemokine Receptor CCR2 Is Not Essential for the Development of Experimental Cerebral Malaria Infect. Immun., June 1, 2003; 71(6): 3648 - 3651. [Abstract] [Full Text] [PDF]
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E. Belnoue, M. Kayibanda, J.-C. Deschemin, M. Viguier, M. Mack, W. A. Kuziel, and L. Renia CCR5 deficiency decreases susceptibility to experimental cerebral malaria Blood, June 1, 2003; 101(11): 4253 - 4259. [Abstract] [Full Text] [PDF]
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J. W. Lillard Jr, U. P. Singh, P. N. Boyaka, S. Singh, D. D. Taub, and J. R. McGhee MIP-1alpha and MIP-1beta differentially mediate mucosal and systemic adaptive immunity Blood, February 1, 2003; 101(3): 807 - 814. [Abstract] [Full Text] [PDF]
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 W. G. Glass and T. E. Lane Functional Expression of Chemokine Receptor CCR5 on CD4+ T Cells during Virus-Induced Central Nervous System Disease J. Virol., December 6, 2002; 77(1): 191 - 198. [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]
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F. J. D. Mennechet, L. H. Kasper, N. Rachinel, W. Li, A. Vandewalle, and D. Buzoni-Gatel Lamina Propria CD4+ T Lymphocytes Synergize with Murine Intestinal Epithelial Cells to Enhance Proinflammatory Response Against an Intracellular Pathogen J. Immunol., March 15, 2002; 168(6): 2988 - 2996. [Abstract] [Full Text] [PDF]
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A. Nansen, J. P. Christensen, S. O. Andreasen, C. Bartholdy, J. E. Christensen, and A. R. Thomsen The role of CC chemokine receptor 5 in antiviral immunity Blood, February 15, 2002; 99(4): 1237 - 1245. [Abstract] [Full Text] [PDF]
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B. P. Chen, W. A. Kuziel, and T. E. Lane Lack of CCR2 Results in Increased Mortality and Impaired Leukocyte Activation and Trafficking Following Infection of the Central Nervous System with a Neurotropic Coronavirus J. Immunol., October 15, 2001; 167(8): 4585 - 4592. [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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 H.-J. ANDERS, V. VIELHAUER, M. KRETZLER, C. D. COHEN, S. SEGERER, B. LUCKOW, L. WELLER, H.-J. GRÖNE, and D. SCHLÖNDORFF Chemokine and Chemokine Receptor Expression during Initiation and Resolution of Immune Complex Glomerulonephritis J. Am. Soc. Nephrol., May 1, 2001; 12(5): 919 - 931. [Abstract] [Full Text]
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Y. Kim, S.-s. J. Sung, W. A. Kuziel, S. Feldman, S. M. Fu, and C. E. Rose Jr Enhanced Airway Th2 Response After Allergen Challenge in Mice Deficient in CC Chemokine Receptor-2 (CCR2) J. Immunol., April 15, 2001; 166(8): 5183 - 5192. [Abstract] [Full Text] [PDF]
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J. W. Lillard Jr., P. N. Boyaka, D. D. Taub, and J. R. McGhee RANTES Potentiates Antigen-Specific Mucosal Immune Responses J. Immunol., January 1, 2001; 166(1): 162 - 169. [Abstract] [Full Text] [PDF]
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W. Peters, M. Dupuis, and I. F. Charo A Mechanism for the Impaired IFN-{gamma} Production in C-C Chemokine Receptor 2 (CCR2) Knockout Mice: Role of CCR2 in Linking the Innate and Adaptive Immune Responses J. Immunol., December 15, 2000; 165(12): 7072 - 7077. [Abstract] [Full Text] [PDF]
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J. A. MacLean, G. T. De Sanctis, K. G. Ackerman, J. M. Drazen, A. Sauty, E. DeHaan, F. H. Y. Green, I. F. Charo, and A. D. Luster CC Chemokine Receptor-2 Is Not Essential for the Development of Antigen-Induced Pulmonary Eosinophilia and Airway Hyperresponsiveness J. Immunol., December 1, 2000; 165(11): 6568 - 6575. [Abstract] [Full Text] [PDF]
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B. T. Fife, G. B. Huffnagle, W. A. Kuziel, and W. J. Karpus Cc Chemokine Receptor 2 Is Critical for Induction of Experimental Autoimmune Encephalomyelitis J. Exp. Med., September 18, 2000; 192(6): 899 - 906. [Abstract] [Full Text] [PDF]
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M. Petrek, J. ZLÁMAL, K. I. WELSH, M. BUNCE, and R. BOIS CC Chemokine Receptor Gene Polymorphisms in Czech Patients with Pulmonary Sarcoidosis Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): 1000 - 1003. [Abstract] [Full Text]
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N. Sato, S. K. Ahuja, M. Quinones, V. Kostecki, R. L. Reddick, P. C. Melby, W. A. Kuziel, and S. S. Ahuja Cc Chemokine Receptor (Ccr)2 Is Required for Langerhans Cell Migration and Localization of T Helper Cell Type 1 (Th1)-Inducing Dendritic Cells: Absence of Ccr2 Shifts the Leishmania major-Resistant Phenotype to a Susceptible State Dominated by Th2 Cytokines, B Cell Outgrowth, and Sustained Neutrophilic Inflammation J. Exp. Med., July 17, 2000; 192(2): 205 - 218. [Abstract] [Full Text] [PDF]
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J. M. Strizki, S. Xu, N. E. Wagner, L. Wojcik, J. Liu, Y. Hou, M. Endres, A. Palani, S. Shapiro, J. W. Clader, et al. SCH-C (SCH 351125), an orally bioavailable, small molecule antagonist of the chemokine receptor CCR5, is a potent inhibitor of HIV-1 infection in vitro and in vivo PNAS, October 23, 2001; 98(22): 12718 - 12723. [Abstract] [Full Text] [PDF]
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