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From the Department of Pathology,* University ofMichigan Medical School, Ann Arbor, Michigan; the Rega Institute forMedical Research, Leuven, Belgium; andAnorMED, Incorporated, Langley, BritishColumbia, Canada
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Abstract |
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levels
within the lungs of treated allergic mice. Furthermore, there
was a significant alteration in the local chemokine production of CCL22
(MDC) and CCL17 (TARC), two chemokines previously shown to be
important in Th2-type allergen responses. Overall, specifically
blocking CxCR4 using AMD3100 reduced a number of pathological
parameters related to asthmatic-type inflammation.
Initially, the targeting of chemokines was thought to be straightforward, however, the identification of multiple chemokines and receptors have, at the very least, complicated the issue. Originally, it was perceived that the targeting of eosinophil-specific factors and their receptors, predominantly eotaxin and CCR3, might have the greatest impact on development of severe disease. However, the realization that Th subsets, Th1 and Th2, may preferentially express specific chemokine receptors suggested that these cell types could be targeted and alter the recruitment of specific T cell subsets.15-18 The Th1 cell subset has been shown to preferentially express CxCR3 and CCR5, whereas Th2 subsets express CCR3, CCR4, CCR8, and CxCR4. Although many of these observations have come from in vitro analysis of cytokine-skewed responses, recent observations in animal models and in human asthma studies have begun to confirm some of these issues.19,20 Of these Th2 cell-expressed chemokine receptors, only CxCR4, and its ligand SDF-1, have been shown to be relevant during Th2-type allergic airway responses.21 CxCR4, like many chemokine receptors, is a Gi-coupled receptor that is specific for SDF-1.22,23 SDF has previously been shown to be chemotactic for a number of leukocyte populations, including neutrophils, monocytes, lymphocytes, and more recently, eosinophils.24-29 Although G-protein-coupled receptors are a pharmaceutically attractive target, few compounds have been shown to be effective during in vivo studies. The studies outlined in this report investigated the use of a soluble CxCR4 inhibitor, AMD3100, in the allergic lung inflammatory responses. This compound has been shown to be effective and specific for blocking human immunodeficiency virus entry into CxCR4-positive cells30,31 and has further proven to be safe in phase I clinical trials.32 In a more recent study, AMD3100 was shown to specifically inhibit SDF-1-mediated responses and alter collagen type 1 model of arthritis in mice.33 Thus, this antagonist may provide for an effective means to block allergen-induced airway inflammation and hyperreactivity.
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Materials and Methods |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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Female CBA/J mice were purchased from the Jackson Laboratories (Bar Harbor, ME) and were maintained under standard pathogen-free conditions
Sensitization and Induction of the Airway Response
To induce a Th2-type response, normal mice were sensitized and challenged with cockroach allergen as previously described.34-36 Briefly, mice were immunized with 10 µg of cockroach allergen (Bayer Corp., Elkhart, IN) in incomplete Freund’s adjuvant on day 0. To localize the response to the lung the mice were given an intranasal administration of 10 µg of cockroach allergen in 10 µl of diluent on day 14. This initial intranasal challenge with antigen induced little cellular infiltrate. Mice were then challenged 6 days later by intratracheal administration of 10 µg of cockroach allergen in 50 µl of sterile.
Delivery of AMD3100
In our initial experiments a bolus injection of AMD3100 was
administered intraperitoneally at various concentrations (0.1, 1, or 10
mg/kg, in 250 µl). AMD3100 was dissolved in saline and a
saline control injection was administered in the control mice. AMD3100
was also used in chronic allergen models and levels needed to be
maintained for 
72 hours. To ensure sufficient levels of the
antagonist throughout the 72-hour experimental period, we used osmotic
Alzet (Alza Corporation, Palo Alto, CA) pumps to deliver AMD3100
at a constant rate of 250 µg/kg/hour. The Alzet (Alza) pumps loaded
with AMD3100 or saline were implanted into the peritoneum of allergic
mice 1 hour before initial intratracheal allergen challenge.
Morphometric Analysis of Airway and Peribronchial Eosinophil Accumulation
To assess migration of eosinophils into the airway, we subjected the mice to a 1-ml bronchoalveolar lavage with phosphate-buffered saline (PBS) containing 25 mmol/L of ethylenediaminetetraacetic acid at various time points after challenge. The cells were then dispersed using a cytospin (Shandon Scientific, Runcorn, UK) and differentially stained with Wright-Giemsa stain. The cell types (mononuclear phagocytes, lymphocytes, neutrophils, and eosinophils) were expressed as a percentage based on 200 total cells counted/sample. Lung tissue was preserved with 4% paraformaldehyde at various time points after challenge. The fixed lungs were embedded in paraffin and multiple 50-µm sections were differentially stained with Wright-Giemsa for the identification of eosinophils and viewed at x1000. The individual eosinophils were counted from 100 high-powered fields per lung at each time point using multiple step sections of lung. The eosinophils counted were only in the peribronchial region, this assured the enumeration of only those eosinophils within or immediately adjacent to an airway. The inflammation observed in this model was completely associated with the airway with little or no alveolitis.
Quantitation of Inflammatory Mediators by Specific Enzyme-Linked Immunosorbent Assay (ELISA)
The levels of cytokine and chemokine proteins in whole-lung
homogenate and from cell-free supernatants were measured by specific
ELISA. The interleukin (IL)-4, IL-5, eotaxin, and IL-12/23 (p40
subunit) antibodies were purchased and pretested by the company (R & D
Systems, Rochester, MN), whereas interferon (IFN)-, CCL7, and
CCL22 were set up using previously described methodology with
antibodies made by our laboratory.19,35,37
Briefly, lung
tissue was homogenized on ice using a tissue-tearor (Biospec Products,
Racine, WI) for 30 seconds in 1 ml of PBS containing 0.05% Triton
X-100. The resulting supernatant was isolated after centrifugation
(10,000 x g). Flat-bottomed 96-well microtiter plates
(Nunc Immunoplate I 96-F; Nunc, Roskilde, Denmark) were coated with 50
µl/well of rabbit polyclonal antibodies, specific for the
cytokine/chemokine in question, for 16 hours at 4°C and then washed
with PBS and 0.05% Tween 20. Nonspecific binding sites were blocked
with 2% bovine serum albumin in PBS and incubated for 90 minutes at
37°C. Plates were rinsed four times with wash buffer and cell-free
supernatants were added (neat and 1/10) followed by incubation for 1
hour at 37°C. Plates were washed four times, a secondary,
biotinylated cytokine-specific antibody was added for 30 minutes,
followed by four washes. In a final step, streptavidin-peroxidase
conjugate (Bio-Rad, Richmond, CA) was added, and the plates were
incubated for 30 minutes at 37°C. Plates were washed again and
chromogen substrate (Bio-Rad) was added and incubated at room
temperature to the desired extinction. The reaction was terminated with
50 µl/well of 3 mol/L of
H2SO4 solution and the
plates were read at 490 nm in an ELISA reader. Standards were 0.5-log
dilutions of recombinant protein from 1 pg/ml to 100 ng/ml. The ELISAs
with purchased reagents were sensitive to 10 pg/ml; whereas the ELISAs
developed using our own reagents were sensitive to 50 pg/ml.
Measurement of Airway Hyperreactivity
Airway hyperreactivity was measured using a Buxco mouse
plethysmograph, which is specifically designed for the low tidal
volumes (Buxco, Troy, NY) as previously
described.34-36,38
Briefly, the mouse to be tested
was anesthetized with sodium pentobarbital and intubated via
cannulation of the trachea with an 18-gauge metal tube. The mouse was
subsequently ventilated with a Harvard pump ventilator (tidal
volume = 0.2 ml, frequency = 120 breaths/minute, positive
end-expiratory pressure 2.0 to 2.5 cm H2O) and
the tail vein was cannulated with a 27-gauge needle for injection of
the methacholine challenge. The plethysmograph was sealed and readings
were monitored by computer. The trachea transducer was calibrated at a
constant pressure of 20 cmH2O. Resistance is
calculated by the Buxco software by dividing the change in pressure
(Ptp) by the change in flow (F)
(tp/F; units =
cmH2O/ml/second) at two time points from the
volume curve based on a percentage of the inspiratory volume. The mouse
was attached to the box and ventilated for 5 minutes before acquiring
readings. Once baseline levels were stabilized and initial readings
were taken, a methacholine challenge was given via the cannulated tail
vein. After determining a dose-response curve (10 to 500 µg/kg), an
optimal dose was chosen, 100 µg/kg of methacholine. This dose was
used throughout the rest of the experiments in this study and induced
little change in resistance in normal, nonallergic mice. After the
methacholine challenge, the response was monitored and the peak airway
resistance was recorded as a measure of airway hyperreactivity.
Flow Cytometric Analysis of Lung T Lymphocytes
Flow cytometric analysis of lymphocyte subsets was performed in dispersed lung samples from normal and cockroach allergen-challenged mice. Lung homogenate leukocyte numbers were determined by enumerating the total cell number multiplied by the percentage of total lung leukocytes (as determined by differential cell staining) or individual subsets, such as CD4 or CD8 T lymphocytes as previously described.39 The fluorescent staining procedure was performed on ice in Dulbecco’s phosphate-buffered saline (D-PBS) with 2% fetal bovine serum and 0.1% sodium azide. Total cells (1 x 106) were stained in 500 µl of buffer. Pelleted cells (5 minutes, 1400 rpm) were incubated for 30 minutes on ice with specific antibody, anti-CD4, anti-CD8, or a subclass control (Pharmingen, La Jolla, CA) directly conjugated with fluorescein isothiocyanate. After incubation an additional 2 ml of cold D-PBS was added and the cells pelleted by centrifugation (5 minutes at 1400 rpm at 4°C). The pelleted cells were washed twice with D-PBS and resuspended in 100 µl of 1% paraformaldehyde for 15 minutes. After incubation the cells were centrifuged with the addition of 2 ml of D-PBS and stored at 4°C in D-PBS containing 0.1% sodium azide until analyzed by flow cytometry. Cells were analyzed within 24 hours of staining procedure.
Statistics
Statistical significance was determined using analysis of variance with P values <0.05.
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Results |
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Previous data has shown that blocking CxCL12 (SDF-1) can
significantly alter airway responses. Thus, the inhibition of CXCR4 may
have a significant effect on the induction of AHR because of its
presence on Th2-type cells as well as on other cell populations
involved in allergic responses. The ability of AMD3100 to block
development of allergen-induced AHR was examined using various doses
given intraperitoneally immediately before (within 15 minutes) a single
allergen rechallenge. The data in Figure 1
indicates that AMD3100 has activity for
inhibition of airway hyperreactivity over a broad range of doses.
Although the effect of inhibiting airway hyperreactivity was diminished
slightly at the lowest dose (0.1 mg/kg) it still demonstrated a
significant decrease in airway hyperreactivity at 24 hours after
allergen challenge. In separate studies a lower dose of AMD3100 (0.01
mg/kg) had no significant effect on the response (data not shown).
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indicates that treatment of the mice
with AMD3100 (250 µg/kg/hour), via the Alzet osmotic pump,
significantly reduces the severity of the airway hyperreactivity
response. Thus, these results correspond to the above data using a
single allergen challenge and may allow a more chronic exposure
protocol to be assessed.
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Because AMD3100 is specifically directed toward CxCR4, a chemokine
receptor involved in leukocyte recruitment, we next examined whether
there was an alteration in total leukocyte infiltrates and, if so,
which subsets were affected? We observed a significant alteration in
the accumulation of peribronchial and airway eosinophils during the
chronic allergen model in the AMD3100 treatment group (Figure 3)
. These changes can be readily observed
by histological examination of the lungs from the treated animals
(Figure 4)
. In addition, the histology
indicates an overwhelming inhibition in the overall inflammatory
response. The alteration in peribronchial eosinophil accumulation and
the histologically apparent alteration in the overall accumulation of
cells suggested an across-the-board effect on recruitment.
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demonstrates that AMD3100 significantly decreased the total number of
leukocytes that were migrating into the lungs of chronically challenged
allergic mice. We also examined whether AMD3100 altered particular T
cell populations. The collagenase-dispersed lung samples from above
were used for flow cytometric analysis and lymphocyte subsets were
examined. The data in Figure 5B
indicates that treatment of allergic
mice with AMD3100 altered CD4+ cell content based on percentage of
total cells that migrated into the lungs. In addition, the ratio of
CD4:CD8 T cells was significantly reduced (P <
0.05). Together with the overall decrease in inflammation, these data
strongly suggest that blocking CxCR4 with AMD3100 affects the T cell
numbers and ratios of subsets and likely all subsequent responses,
including eosinophil accumulation and airway hyperreactivity.
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In these latter studies we also assessed the local cytokine
responses in the lungs of the challenged animals. The ability to reduce
the appropriate cytokines (Th2 type), while increasing others (Th1
type) may be the most effective strategy to alter the long-term effects
of asthmatic disease. Analysis of pulmonary levels of Th1-associated
(IL-12 p40 subunit and IFN-) and Th2-associated (IL-4 and IL-5)
cytokines indicates that AMD3100 clearly affected the cytokine profile
of the lungs after multiple allergen challenges (Figure 6)
. Both IL-4
and IL-5 were significantly decreased, whereas IL-12 (p40 subunit) and
IFN- were significantly increased after multiple allergen challenges
in the AMD3100 treatment group. These data indicate that the phenotype
of the response was drastically altered from a predominant Th2 allergic
response to a more clinically attractive Th1-type response. These data
help explain why there were fewer eosinophils and lower airway
hyperreactivity responses.
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illustrates that when we examined CCL11
(CCR3 ligand), CCL17, and CCL22 (CCR4 ligands), both CCL17 and
CCL22 were significantly reduced in the AMD3100-treated group. These
data indicated that along with the Th2-type cytokines, chemokines were
also significantly reduced, correlating with the overall reduction of
inflammation and airway hyperreactivity.
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Discussion |
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TopAbstractMaterials and MethodsResultsDiscussionReferences |
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down-regulates CxCR4 expression on the surface of T
lymphocytes.18,40-42
In further support are studies
indicating that Th1-type lymphocytes have very little or no expression
of CxCR4, whereas Th2-type lymphocytes express CxCR4 on their
surface.20,41
In agreement with our data is a recent study
that indicates that SDF-1 and CxCR4 are directly involved in the
asthmatic response in an ovalbumin model of asthma.21
Thus, the role of CxCR4 during an allergic/asthmatic pulmonary response
may reflect the altered immune environment leading to increased lung
damage and airway reactivity. The present experiments add further
information to the possible mechanism of how CxCR4 is involved. When
AMD3100 was administered to the allergic mice Th1-type cytokines were
increased in the lung after allergen rechallenge. These data correlate
well with the inflammation analysis, including decreased peribronchial
eosinophil accumulation and the reduction in total leukocyte
accumulation in allergen-challenged animals, as assessed by lung
dispersion.
The efficacy of AMD3100 was initially tested by measuring the change in
airway resistance in mice after a single allergen challenge. AMD3100
exhibited a broad dose-dependent reduction in airway resistance with
significant activity as low as 0.1 mg/kg. Our subsequent studies were
focused on the effect of AMD3100 during multiple allergen challenges,
which may be more representative of the responses in chronic asthmatics
that constantly are exposed to allergen stimulation. Because we were
concerned with the availability of AMD3100 during chronic allergen
exposure, we also examined the efficacy of giving AMD3100 to animals
via osmotic pumps, thus allowing a constant release instead of a bolus
administration. These studies demonstrated significant decreases in the
airway responses and a striking alteration in the development of the
peribronchial lung inflammation. Of greatest concern in asthmatics are
the long-term consequences of allergen-induced inflammation and damage
to the airway.20,43
Possibly reflecting the responses in
chronic asthmatics, our exposure of animals to multiple allergen
challenges has previously indicated an extreme dependency on lymphocyte
and eosinophil accumulation and activation.34,35,39
The
constant inflammation associated with this response may be the most
devastating long-term problem to these patients. Managing this latter
aspect may be the key to altering the progression of the asthmatic
disease. Using AMD3100, the observed effects were broad-based and
demonstrated several favorable aspects of the response. Firstly, and
probably most importantly, inhibiting CxCR4 with AMD3100 significantly
reduced the airway hyperreactivity response by nearly 50%. Subsequent
experiments indicated an across the board reduction in inflammation,
including a significant reduction in peribronchial and airway
eosinophilia and an alteration in lymphocyte and mononuclear phagocyte
numbers. In fact, the analysis of total leukocytes indicated that there
was an 80% reduction in recruited leukocytes over background
numbers in AMD3100-treated animals compared to control saline-treated
animals. This effect may be because of blocking CxCR4 interactions on
multiple cell populations, including lymphocytes and eosinophils, both
of which have been described to express CxCR4.29,44
In
addition, recent studies have identified CxCR4 on basophils, and its
ligand, SDF-1, was able to induce activation and degranulation of those
cells.45
However, the data from the present studies may
build the strongest case for alteration of T cell accumulation and
activation, based on the alteration of the cytokine profiles. Previous
studies have clearly indicated that administration of IL-12 and/or
IFN- in the lungs attenuates airway hyperreactivity induced by
allergens.46-48
The results from these studies not only
demonstrated that IL-12 (p40 subunit) and IFN- levels were
increased, but the administration of the CxCR4 antagonist, AMD3100,
reduced IL-4 and IL-5 levels. This shift toward Th1-type cytokines may
be the most favorable response because previous studies have
demonstrated that Th2 cell transfer increases airway hyperreactivity,
whereas transfer of Th1-type cells does not increase or alter airway
hyperreactivity even though a significant response to allergen is
observed.5,49
Thus, the Th1-type cytokines, although
possibly damaging, do not promote an asthmatic-type response on their
own. Altogether, the alteration of cytokine profiles constitute a
significant aspect of this compound that throughout time could reduce
the airway damage and inflammation in patients that potentially leads
to end-stage disease.
The role of chemokines in asthma is central to the chronic recruitment of leukocytes that migrate into and around the airway during asthmatic responses. A number of chemokines have been identified as possible targets using animal models of asthma and hyperreactivity, including CCL2 (MCP-1), CCL7 (MCP-3), CCL11 (eotaxin), CCL17 (TARC), CCL22 (MDC), and CxCL12 (SDF-1).14,34,35,39,50-52 The reduction of CCL17 and CCL22 after blocking CxCR4 may represent an additional aspect of the attenuated response. The reduction of these chemokine mediators may be a direct result of the alteration of the T cell-derived cytokines, Th1 versus Th2. A number of chemokine receptors have also been shown to be important in the development of the airway responses, including CCR1, CCR2, and CCR8.53-55 Relevant data for blocking other receptors, such as CCR3 and CCR4, are still lacking. However, it is likely that multiple receptors contribute to the recruitment of the various cell populations that migrate into the airways after allergen challenge. It seems that CxCR4 may be a pivotal receptor used during the allergen-induced responses. The anti-inflammatory response observed with AMD3100 treatment has been observed in a previous publication using a type I collagen-induced arthritis model,33 but no alteration in specific subsets was seen. The present study seems to demonstrate an altered immune environment that may be because of an overall decrease in inflammation as observed in the arthritis model. In addition, CxCR4 has a significant role in leukocyte maturation in the bone marrow.56 Thus, further studies will need to more thoroughly address whether AMD3100 has an effect on leukocyte differentiation in the bone marrow.
The specific CxCR4 inhibitor used in these studies, AMD3100, has been shown to specifically inhibit human immunodeficiency virus entry into cells via blocking CxCR4 interactions.30,31 The pharmacokinetics and safety have already been assessed in humans and AMD3100 was found to be well tolerated.32 There are a number of observations from the present studies that may be advantageous in other diseases as well, including the skewing of the immune response from Th2- toward a Th1-type response. Altogether, these data indicate that AMD3100 may be a desirable compound to pursue in clinical trials for efficacy in asthmatic patient populations.
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Footnotes |
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Supported in part by National Institutes of Health grants AI36302 and HL31963.
Accepted for publication January 4, 2002.
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