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Departments of Medicine and Ophthalmology, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106
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was localized to the corneal stroma, rather than to the
epithelium, which was consistent with the location of neutrophils in
the cornea. CCR1 deficiency did not inhibit neutrophil or eosinophil
infiltration to the cornea or development of corneal opacification. In
marked contrast, neutrophil recruitment to the corneas of
CXCR2-/- mice was significantly impaired
(p < 0.0001 compared with control, BALB/c mice)
with only occasional neutrophils detected in the central cornea.
Furthermore, CXCR2-/- mice developed only mild corneal
opacification compared with BALB/c mice. These differences were not due
to impaired KC and MIP-2 production in the corneal stroma of
CXCR2-/- mice, which was similar to BALB/c mice.
Furthermore, although MIP-1 production was lower in
CXCR2-/- mice than BALB/c mice, eosinophil recruitment to
the cornea was not impaired. These observations demonstrate the
critical role for CXCR2 expression in neutrophil infiltration to the
cornea and may indicate a target for immune intervention in
neutrophil-mediated corneal inflammation. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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selectively
induce neutrophil chemotaxis and activation, whereas the activity of
C-C chemokines is generally targeted to mononuclear cells and
eosinophils (2, 3). However, neutrophils also express
CCR1, which responds to CC chemokines, such as macrophage-inflammatory
protein (MIP)3-1
(4). MIP-1 activates neutrophils in vitro
(4) and in vivo, as intradermal injection of MIP-1
induces rapid infiltration of neutrophils to the skin (5).
Furthermore, CCR1 gene knockout mice are more susceptible to
neutrophil-mediated pulmonary aspergillosis (6), and
neutrophil recruitment to the cornea is impaired in MIP-1-deficient
mice infected with herpes simplex virus (7).
Human neutrophils express two IL-8Rs, CXC chemokine receptor (CXCR)-1
and CXCR2. Whereas CXCR1 is specific for IL-8 and has no known murine
homologue, CXCR2 binds several CXC chemokines and has a
well-characterized murine homologue that binds MIP-2 and KC
(8). As with CCR1-MIP-1 interactions, blockade of
CXCR2-mediated interactions impairs neutrophil infiltration and
development of tissue damage (9, 10, 11, 12, 13, 14). We have used a
murine model of ocular onchocerciasis (river blindness) to identify
immune mediators of neutrophil and eosinophil recruitment to the cornea
(reviewed in (15, 16)). In this model, animals are
immunized s.c. and injected into the corneal stroma with Ags from the
parasitic worm Onchocerca volvulus. Mice develop severe
corneal opacification, which is associated with a biphasic pattern of
granulocyte recruitment to the cornea, where neutrophils are the most
prominent cell type in the first 24 h, and are replaced by
eosinophils after 72 h (15, 16, 17).
In the current study, we used gene knockout mice to determine the relative contribution of the murine IL-8R homologue (CXCR2) and CCR1 in recruitment of neutrophils to the cornea. Because CCR1 is expressed on eosinophils in addition to neutrophils, we also examined the effect of chemokine receptor deficiency on eosinophil recruitment.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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IL-8R homologue (CXCR2)-deficient (BALB/c-Cmkar2) mice were obtained from The Jackson Laboratory (Bar Harbor, ME). These mice were generated by a targeted mutation of chemokine (C-X-C) receptor 2 (18). Age- and sex-matched BALB/c mice were obtained from The Jackson Laboratory as controls. CCR1 gene knockout mice were generated as described (6) and kindly provided by Dr. Phil Murphy at the National Institutes of Health. Age- and sex-matched C57BL/6 mice were obtained from The Jackson Laboratory as controls.
Parasite Ags
O. volvulus worms were obtained from nodules that had been surgically removed from patients in Cameroon and were kindly provided by Dr. Jan Bradley at the University of Nottingham (Nottingham, U.K.). Soluble O. volvulus Ags were prepared as described previously (19). Briefly, worms were isolated from s.c. nodules after digestion with collagenase (Sigma, St. Louis, MO). Parasites were homogenized in HBSS, sonicated briefly, and centrifuged to remove insoluble material. O. volvulus Ag preparation were adjusted to 2 mg/ml and stored at -70°C.
Immunization and injection into the corneal stroma
Mice received three weekly s.c. immunizations with 10 µg O. volvulus Ags in a 1:1 ratio with adjuvant containing squalene (Aldrich Chemical, Milwaukee, WI), Tween 80 (Fisher, Fair Lawn, NJ), and pluronic acid (BASF Bioresearch, Cambridge, MA). For intrastromal injections, the cornea was scarified with a 30-gauge needle, and 5 µg O. volvulus Ags were injected into the corneal stroma using a 33-gauge needle attached to a Hamilton syringe (Hamilton, Reno, NV). Corneal opacification was monitored daily by slit lamp examination and evaluated as previously described (19).
Detection of chemokines in the corneal stroma and epithelium
To determine the concentration of chemokines in murine corneas,
animals were sacrificed and corneas were carefully dissected to avoid
removing surrounding conjunctival tissue and underlying iris. Corneas
were then incubated in 20 mM Na EDTA for 1 h at
37OC, which separates the epithelial cell layer
from the underlying stroma. The stroma and epithelium were physically
separated using fine-tip forceps, suspended in 400 µl RPMI 1640
medium, and sonicated 90 s at 50 cycles/s (Sonics VibraCell,
Danbury, CT). MIP-2, KC, and MIP-1 were detected in supernatants by
two-site ELISA following manufacturer’s directions (R&D Systems,
Minneapolis, MN). The limit of detection for MIP-2 and MIP-1 was 1.5
pg/ml, and 2.0 pg/ml for KC.
Detection of neutrophils and eosinophils in the cornea by immunohistochemistry
Eyes were removed, fixed for 8 h in 10% formaldehyde (Sigma), processed, and embedded in paraffin by standard methods. To detect neutrophils, 5-µm sections were immunostained with mAb NIMP-R14 diluted 1:100, followed by biotinylated rabbit anti-rat Ig (BioGenex Laboratories, San Ramon, CA). Eosinophils were detected using rabbit antisera to major basic protein diluted 1:5000 for 2 h as described (20). After incubation with a secondary Ab, sections were incubated with alkaline phosphatase conjugated streptavidin (BioGenex Laboratories). Positive reactivity was visualized using Vector Red Substrate (Vector Laboratories, Burlingame, CA) containing Levamisole (Sigma), and counterstained with modified Harris’ hematoxylin (Richard-Allen, Kalamazoo, MI). Cells in the cornea were visualized by bright field and fluorescent microscopy and counted by a masked observer.
Measurement of Ab responses
Sera were collected at the time of sacrifice and assayed for Ab by ELISA. Immulon-4 ELISA plates (Dynatech Laboratories, Chantilly, VA) were coated with 50 µl of 1 µg/ml parasite Ags and incubated overnight at 4°C. After blocking with 1% fetal bovine sera, dilutions of mouse sera were incubated 2 h at room temperature, washed, and incubated with biotinylated goat anti-mouse isotype-specific Abs (Southern Biotechnology Associates, Birmingham, AL). Reactivity was determined after incubation with peroxidase-labeled anti-goat IgG (Santa Cruz Biotechnology, Santa Cruz, CA), and tetramethyl benzidine (Zymed, San Francisco, CA) was used as a substrate. The reaction was stopped after 10 min with 1 N HCl, and absorbance was measured at 450 nm on a kinetic microplate reader (Molecular Devices, Sunnyvale, CA).
For quantitation of total serum IgE, Immulon 4 plates were coated with an anti-mouse IgE mAb R35-72 (BD PharMingen, San Diego, CA). Biotinylated anti-mouse IgE monoclonal R35-92 (BD PharMingen) was used as the detecting Ab, followed by streptavidin peroxidase (Sigma). O-phenylenediamine (Cirex, Warrington, PA) was used as a substrate. The reaction was stopped with 10% sulfuric acid and absorbance was measured at 490 nm. A standard curve was generated using purified mouse IgE (BD PharMingen).
Statistics
Statistical significance was determined using an unpaired t test (PRISM Graph Pad Software, San Diego, CA). A value of p < 0.05 was considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in the corneal stroma and
epithelium
Migration of neutrophils and eosinophils from peripheral, limbal
vessels to the central corneal stroma in O. volvulus
keratitis occurs in a biphasic manner, with neutrophils appearing
within 24 h after injection of parasite Ags and declining by
72 h (17, 20). In contrast, eosinophils are rarely
detected before 24 h and reach maximal numbers after 72 h. To
determine whether production of MIP-1, MIP-2, and KC in the cornea
is temporally associated with infiltration of neutrophils and
eosinophils, and to determine whether these chemokines are produced by
cells in the corneal epithelium or stroma, BALB/c mice were immunized
s.c. and injected into the corneal stroma with O. volvulus
Ags. Six, 24, and 72 h later, corneas were dissected, corneal
epithelial and stromal layers were separated and disrupted by
sonication, and chemokine production was determined by ELISA.
As shown in Fig. 1
, baseline production
of each chemokine (in naive controls) was below the level of detection
of the assays. However, after injection of parasite Ags, cells in the
corneal stroma produced MIP-1, MIP-2, and KC, whereas with the
exception of KC produced at 6 h, these chemokines were not
detected in the corneal epithelium. Within 6 h of intrastromal
injection of parasite Ags, MIP-2 and KC production in the stroma was
>100 pg/ml. MIP-2 production remained elevated at 24 h, but had
declined by 72 h, whereas KC production had decreased by 24
h. In contrast to MIP-2 and KC, >40 pg/ml MIP-1 was detected at
6 h after intrastromal injection but increased to >200 pg/ml by
24 h.
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production may indicate a role for this chemokine in eosinophil
recruitment. CCR1 expression is not essential for infiltration of neutrophils or eosinophils to the corneal stroma
Because CCR1 is the primary receptor for MIP-1 on neutrophils
and CCR1 is expressed on neutrophils and eosinophils, we first
determined the role of CCR1 on cell recruitment to the cornea. C57BL/6
and CCR1-/- mice were immunized s.c. and
injected intrastromally with parasite Ags, and the number of
neutrophils and eosinophils in the corneal stroma was determined after
24 and 72 h. Consistent with previous observations in C57BL/6 mice
(17, 20), neutrophils were present throughout the corneas
after 24 h, and eosinophils were present at 72 h (Fig. 2). There was no significant difference
in neutrophil or eosinophil numbers between
CCR1-/- mice and control C57BL/6 mice,
indicating that CCR1 expression is not essential for recruitment of
neutrophils or eosinophils to the cornea.
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Because CXCR2 is the receptor for KC and MIP-2 on murine neutrophils, we next determined the role of this receptor in recruitment of neutrophils to the cornea. BALB/c mice and CXCR2-/- mice (on a BALB/c background) were immunized and injected intrastromally with parasite Ags as described above.
As shown in Figs. 3 and 4, neutrophils were present throughout
the corneal stroma of BALB/c mice, similar to that described above for
C57BL/6 mice. In marked contrast to BALB/c mice, infiltration of
neutrophils to the peripheral region of
CXCR2-/- corneas was significantly impaired,
and only occasional neutrophils were detected in paracentral and
central regions (Figs. 3 and 4). These observations demonstrate an
essential role for CXCR2 in recruitment of neutrophils to the cornea.
Furthermore, neutrophils were detected in the corneal stroma but not in
the epithelium (Fig. 4), consistent with the site of production of
neutrophil chemokines MIP-2, KC, and MIP-1.
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Our previous studies indicated that neutrophils are likely to mediate keratitis in the first 24 h after injection of parasite Ags into the cornea (17, 20, 21). To determine the effect of CXCR2 expression on development of keratitis, BALB/c and CXCR2-/- mice were immunized s.c. and injected intrastromally with O. volvulus Ags as described above. Corneas were examined by slit lamp microscopy and scored according to the intensity of opacification.
As shown in Fig. 5, BALB/c mice developed
pronounced corneal opacification after injection of parasite Ags.
CXCR2-/mice developed mild corneal opacities, and
the clinical scores were significantly lower than were those of BALB/c
mice (p < 0.0001). There was no significant
effect of CCR1 deficiency on corneal opacification (data not
shown).
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Because parasite-specific IgG production is essential for
neutrophil recruitment to the cornea in O. volvulus
keratitis (20) and because
CXCR2-/- mice have altered B cell responses
(10, 18), we determined whether parasite-specific IgG1 and
IgG2a production was modified in CXCR2-/- mice.
As shown previously for C57BL/6 mice (20), BALB/c mice had
elevated parasite-specific IgG1 compared with IgG2a (Fig. 6), consistent with a predominant Th2
response. However, despite reports that B cell numbers are elevated in
CXCR2-/- mice (18), there was no
effect of CXCR2 deficiency on production of these isotypes in response
to parasite Ags. Interestingly, total serum IgE was significantly
elevated in CXCR2-/- mice
(p = 0.014), consistent with previous
observations in a model of airway hyperresponsiveness
(10). However, given that neutrophils do not express
either high or low affinity IgE receptors (22), it is
unlikely that differences in the systemic response of these mice
contribute to the marked impairment of neutrophil infiltration and
corneal opacification in CXCR2-/-
mice.
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As neutrophils have been shown to produce chemokines
(23, 24, 25), we predicted that if these cells are a major
source of chemokines in O. volvulus keratitis, chemokine
production in the corneal stroma of CXCR2-/-
mice would be significantly lower than in control mice. BALB/c and
CXCR2-/- mice were sacrificed 24 h after
injection of parasite Ags (when neutrophils are prominent in BALB/c
corneas), and chemokine production in the corneal stroma was determined
by ELISA. As shown in Fig. 7, MIP-2, KC,
and MIP-1 were produced in the corneal stroma of
CXCR2-/- mice, despite the paucity of
neutrophils (no chemokines were detected in the epithelium). MIP-2
production was not significantly different in
CXCR2-/- mice, whereas KC production was
elevated rather than decreased. MIP-1 production was significantly
lower in CXCR2-/- mice than in BALB/c mice,
although >100 pg/ml MIP-1 was detected in corneas of
CSCR2-/- mice.
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production. CXCR2 deficiency does not impair eosinophil migration to the corneal stroma
Because MIP-1 also stimulates eosinophil migration
(6), we determined whether the reduced level of MIP-1
in CXCR2-/- mice had any effect on eosinophil
recruitment to the cornea. BALB/c and CXCR2-/-
mice were immunized and injected intrastromally as described above,
sacrificed after 72 h, and eosinophils were counted after
immunostaining with Ab to major basic protein. As shown in Fig. 8, there were no significant differences
in eosinophil numbers between BALB/c and
CXCR2-/- mice in any region of the cornea. This
finding indicates that cells in the corneal stroma of
CXCR2-/- mice produce sufficient chemokines
(including MIP-1) to mediate normal eosinophil recruitment.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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production
peaks at 24 h, when neutrophils are already abundant in the
cornea. Consistent with this observation, we found that whereas CCR1
deficiency had no effect on neutrophil infiltration, neutrophil
recruitment to the corneas of CXCR2-/- mice was
significantly diminished.
Our results are in agreement with those reported for another form of
ocular inflammation, endotoxin-induced uveitis, in which neutrophil
infiltration to the uveal tract was significantly impaired in
CXCR2-deficient mice, but not in mice in which the MIP-1 gene was
deleted (9). However, our finding that disruption of
CCR1-MIP-1 interactions has no effect on neutrophil recruitment to
the cornea differ from those of Tumpey and coworkers (7),
who showed that after infection with herpes simplex virus, neutrophil
recruitment to the corneas of MIP-1 gene knockout mice was
significantly impaired. This discrepancy is likely to be due to the
ability of MIP-1 to activate receptors other than CCR1. Neutrophil
recruitment to the cornea is also impaired after in vivo neutralization
of MIP-2 in herpes simplex keratitis (14) and in
Pseudomonas keratitis (11). Our findings are in
agreement with these reports in demonstrating the importance of
CXCR2-MIP-2 interactions in recruitment of neutrophils to the cornea.
Although KC production was elevated in both studies, depletion of this
chemokine did not inhibit neutrophil recruitment to the cornea
(14). The more potent effect of MIP-2 may relate to the
finding that MIP-2 binds this receptor with 10-fold higher affinity
than that of KC (8). Alternatively, the relative
contribution of these chemokines may depend on the tissue involved,
because Abs to KC inhibit neutrophil recruitment to the skin and
development of contact hypersensitivity (28).
Our findings demonstrate that cells in the corneal stroma rather than
in the epithelium are the primary source of these chemokines in
O. volvulus keratitis, because the latter produce <10 pg/ml
of each chemokine compared with up to 300 pg/ml produced by cells in
the corneal stroma. This observation is consistent with the location of
neutrophils in the cornea, which is limited to the stromal area, and
with a report that gro- is produced by stromal fibroblasts rather
than epithelial cells (29). However, our findings differ
from those of Yan and colleagues (14), who reported MIP-2
expression (by immunohistochemical analysis) in the corneal epithelium
in herpes simplex keratitis.
Neutrophils are a major source of chemotactic cytokines, including IL-8
and MIP-1- (23, 24, 25). These cells also have prestored
IL-12 (30), which may contribute to the chemotactic
activity (31). In the current study, the observation that
MIP-2 production is unimpaired in CXCR2-/- mice
and KC production is actually elevated would suggest that neutrophils
are not a major source of these chemokines. Because stromal fibroblasts
(cultured from human corneas) can produce IL-8 and gro- (29, 32), it seems reasonable to assume that in O.
volvulus keratitis, resident stromal fibroblasts are a primary
source of these chemokines before neutrophil infiltration (at 6 h
postinjection). Later, infiltrating cells are likely to be the major
source of chemokines.
In contrast to KC and MIP-2, it is likely that neutrophils contribute
to production of MIP-1. This notion is based on several
observations. First, in contrast to KC and MIP-2 production, which is
rapidly elevated before neutrophil infiltration, peak MIP-1
production was at 24 h, when neutrophils are prominent in the
cornea. Second, MIP-1 production at 24 h is decreased in
CXCR2-/- mice, where there is a paucity of
neutrophils. Third, neutrophils are reported to produce MIP-1
(23, 24, 25). Further studies will determine more directly
which chemokines are produced by neutrophils in the cornea.
Although MIP-1-CCR1 interactions can mediate eosinophil chemotaxis
(6), we found that recruitment of eosinophils to the
corneas of CXCR2-/- mice was unaffected by
diminished MIP-1 production. Taken together with the observation
that CCR1 deficiency had no effect on eosinophil infiltration of the
cornea, we conclude that MIP-1-CCR1 interactions do not play a
critical role in eosinophil recruitment in O. volvulus
keratitis. Because MIP-1 is not completely reduced in
CXCR2-/- mice and because MIP-1 can bind to
other receptors such as CCR3 and CCR5, we cannot eliminate the
possibility that MIP-1 has a role in eosinophil recruitment to the
cornea. These chemokines may also have a role in modulating the
effector function of eosinophils, as shown previously for MIP-1 and
eotaxin (33, 34).
The selective effect of CXCR2 deficiency on neutrophils rather than on eosinophils is similar to an OVA model of airway hyperresponsiveness in which neutrophil recruitment to the lungs was reduced in CXCR2-/- mice, but there was no effect on eosinophil infiltration (10). Expression of IL-8Rs on human eosinophils has been reported (35, 36), although a recent study suggests that those findings may have been due to neutrophil contamination (37). Our observation that there is no difference in eosinophil numbers in the cornea between control and CXCR2-/- mice indicate that if CXCR2 is expressed on murine eosinophils, that it has no direct effect on eosinophil recruitment to the cornea.
In summary, the results of the current study demonstrate that CXCR2 expression is essential for neutrophil recruitment to the cornea and development of O. volvulus keratitis. Because murine and human CXCR2 are homologous, local blockade of CXCR2 could prevent neutrophil-mediated corneal disease in humans. However, because neutrophils are essential for host defense and because blockade of CXCR2 interactions leads to increased growth of bacteria such as Pseudomonas aeruginosa (38) and Nocardia asteroides (39), this approach would only be applicable for noninfectious causes of neutrophil-mediated keratitis.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Eric Pearlman, Division of Geographic Medicine, Case Western Reserve University, 2109 Adelbert Road, W137, Cleveland, OH 44106-4983.
3 Abbreviations used in this paper: MIP, macrophage-inflammatory protein; CXCR, CXC chemokine receptor.
Received for publication October 30, 2000. Accepted for publication January 2, 2001.
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References |
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induces significant recruitment of neutrophils and monocytes. J. Immunol. 164:3392. prevents the development of blinding herpes stromal keratitis. J. Virol. 72:3705., and the chemokines macrophage-inflammatory protein-1 and -1
in response to Toxoplasma gondii antigens. J. Immunol. 162:7369.-mediated recruitment of neutrophils is required for elicitation of contact hypersensitivity. Eur. J. Immunol. 29:3485.[Medline]
gene expression in human corneal epithelial cells and keratocytes exposed to proinflammatory cytokines. Invest. Ophthalmol. Vis. Sci. 38:1149.This article has been cited by other articles:
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T. Persson-Dajotoy, P. Andersson, A. Bjartell, J. Calafat, and A. Egesten Expression and Production of the CXC Chemokine Growth-Related Oncogene-{alpha} by Human Eosinophils J. Immunol., May 15, 2003; 170(10): 5309 - 5316. [Abstract] [Full Text] [PDF]
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A. L. Miller, R. M. Strieter, A. D. Gruber, S. B. Ho, and N. W. Lukacs CXCR2 Regulates Respiratory Syncytial Virus-Induced Airway Hyperreactivity and Mucus Overproduction J. Immunol., March 15, 2003; 170(6): 3348 - 3356. [Abstract] [Full Text] [PDF]
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H. Yamagami, S. Yamagami, T. Inoki, S. Amano, and K. Miyata The Effects of Proinflammatory Cytokines on Cytokine-Chemokine Gene Expression Profiles in the Human Corneal Endothelium Invest. Ophthalmol. Vis. Sci., February 1, 2003; 44(2): 514 - 520. [Abstract] [Full Text] [PDF]
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B. K. Ambati, A. Anand, A. M. Joussen, W. A. Kuziel, A. P. Adamis, and J. Ambati Sustained Inhibition of Corneal Neovascularization by Genetic Ablation of CCR5 Invest. Ophthalmol. Vis. Sci., February 1, 2003; 44(2): 590 - 593. [Abstract] [Full Text] [PDF]
|
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E. Garcia-Ramallo, T. Marques, N. Prats, J. Beleta, S. L. Kunkel, and N. Godessart Resident Cell Chemokine Expression Serves as the Major Mechanism for Leukocyte Recruitment During Local Inflammation J. Immunol., December 1, 2002; 169(11): 6467 - 6473. [Abstract] [Full Text] [PDF]
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S. Khatri, J. H. Lass, F. P. Heinzel, W. M. Petroll, J. Gomez, E. Diaconu, C. M. Kalsow, and E. Pearlman Regulation of Endotoxin-Induced Keratitis by PECAM-1, MIP-2, and Toll-like Receptor 4 Invest. Ophthalmol. Vis. Sci., July 1, 2002; 43(7): 2278 - 2284. [Abstract] [Full Text] [PDF]
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X. Ruan, J. Chodosh, M. C. Callegan, M. C. Booth, T. D. Lee, P. Kumar, M. S. Gilmore, and H. A. Pereira Corneal Expression of the Inflammatory Mediator CAP37 Invest. Ophthalmol. Vis. Sci., May 1, 2002; 43(5): 1414 - 1421. [Abstract] [Full Text] [PDF]
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 A. v. S. Andre, N. M. Blackwell, L. R. Hall, A. Hoerauf, N. W. Brattig, L. Volkmann, M. J. Taylor, L. Ford, A. G. Hise, J. H. Lass, et al. The Role of Endosymbiotic Wolbachia Bacteria in the Pathogenesis of River Blindness Science, March 8, 2002; 295(5561): 1892 - 1895. [Abstract] [Full Text] [PDF]
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A. S. MacDonald, M. I. Araujo, and E. J. Pearce Immunology of Parasitic Helminth Infections Infect. Immun., February 1, 2002; 70(2): 427 - 433. [Full Text] [PDF]
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L. R. Hall, E. Diaconu, and E. Pearlman A Dominant Role for Fc{{gamma}} Receptors in Antibody-Dependent Corneal Inflammation J. Immunol., July 15, 2001; 167(2): 919 - 925. [Abstract] [Full Text] [PDF]
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J. T. Kaifi, E. Diaconu, and E. Pearlman Distinct Roles for PECAM-1, ICAM-1, and VCAM-1 in Recruitment of Neutrophils and Eosinophils to the Cornea in Ocular Onchocerciasis (River Blindness) J. Immunol., June 1, 2001; 166(11): 6795 - 6801. [Abstract] [Full Text] [PDF]
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) and CXCR2-/- (
) mice are
mean ± SEM for five animals per group. There was no significant
difference in IgG1 or IgG2a. Total serum IgE levels were elevated in
CXCR2-/- mice (±SEM for five animals per group).
