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*
Pharmaceutical Research Laboratory, Kirin Brewery Co., Ltd., Gunma, Japan;
Department of Pharmacology, Gifu Pharmaceutical University, Gifu, Japan; and
La Jolla Institute for Allergy and Immunology, San Diego, CA 92121
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It is well established that cross-linking of IgE Abs on mast cells
by Ag triggers the release of chemical mediators which cause immediate
allergic reactions (9, 10, 11). However, the role of mast
cells in the late phase response is not clear, except that the
activation of mast cells leads to the synthesis of IL-4, IL-5, and
TNF-
, which have a potential role in causing inflammation (12, 13). The present experiments were undertaken to determine
possible roles of mast cells in the development of Ag-induced AHR by
making a comparison between mast cell-deficient
W/Wv mice and their congenic littermates. The
results show that when the two strains are immunized with OVA and
exposed to aerosolized Ag under exactly the same protocol,
W/Wv mice fail to develop AHR whereas their
congenic littermates do. The experiments also demonstrate that
reconstitution of W/Wv mice with bone
marrow-derived cultured mast cells restores the ability to develop AHR,
indicating that the lack of mast cells in the
W/Wv strain is responsible for failure of the
strain to develop AHR.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Crystalline OVA was purchased from Seikagaku (Tokyo, Japan). Biotinylation of OVA was conducted using a biotinylation kit (Amersham, Arlington Heights, IL). Standard mouse anti-OVA serum was obtained by immunization of BDF1 mice with aluminum hydroxide gel (alum)-adsorbed OVA. After several booster injections of alum-adsorbed OVA, a pooled antiserum was obtained. Rat anti-mouse IL-5 mAb TRFK-5 (14) and rat IgGl, R3-34 were obtained from PharMingen (San Diego, CA). Anti-mouse IgE mAb 6HD5 (15) was purchased from Yamasa (Tokyo, Japan). Alkaline phosphatase-coupled rabbit anti-mouse IgG1 was purchased from Zymed (San Francisco, CA). Acetylcholine chloride was purchased from Nacalai Tesque (Kyoto, Japan). Pancuronium bromide was purchased from Sigma (St. Louis, MO) and sodium pentobarbitone was purchased from Dainabot (Osaka, Japan).
Animals and immunization
Male BALB/c mice, mast cell-deficient WBB6F1 W/Wv mice, and their congenic normal littermates, i.e., WBB6F1 +/+, were purchased from Japan SLC (Shizuoka, Japan). They were housed under specific pathogen-free conditions, and five to seven mice in a group were immunized by an i.p. injection of 10 µg OVA adsorbed to 1 mg alum. A booster injection of the same dose of alum-adsorbed OVA was given 5 days later. Unimmunized control mice received saline.
Ag bronchoprovocation
Twelve days after primary immunization, both the immunized and unimmunized mice were exposed to aerosolized Ag. Aerosolization of OVA was performed using a nose-only aerosol chamber adapted for mice. Animals were exposed for 10 min to 5 mg/ml OVA aerosolized by an ultrasonic nebulizer (NE-U12; Omron, Tokyo, Japan) driven by a vacuum pump. The Ag bronchoprovocation was repeated on days 16 and 20 under the same conditions. In some experiments, both W/Wv and +/+ mice were immunized and exposed to the aerosolized OVA (10 mg/ml) for 30 min three times per day. In these groups, the Ag bronchoprovocation was repeated every second day from days 12 to 20 under the same conditions.
Determination of airway reactivity
Twenty-four hours after the final aerosol exposure, bronchoconstriction was measured according to the overflow method of Konzett and Rössler (16). Mice were anesthetized by an i.p. injection of sodium pentobarbitone (50 mg/kg), and the tracheas were surgically exposed, cannulated, and connected to a rodent ventilator (model 683; Harvard Apparatus, South Natick, MA) and a bronchospasm transducer (model 7020; Ugo Basile, Comerio-Varese, Italy). Animals were mechanically ventilated with air at 60 strokes/min, with a stroke volume of 0.6 ml. A paralytic agent, pancuronium bromide, 0.1 mg/kg, was administered to eliminate spontaneous respiration. After a stable baseline airway pressure was established, acetylcholine chloride was injected i.v. in a volume of 1 µl/g of mouse/dose, starting with 31.3 µg/kg, and increasing the concentration 2-fold for each subsequent dose. Bronchoconstriction was recorded on a flatbed recorder (model FBR-252A; TOA Electronics, Tokyo, Japan). Bronchoconstriction (percent) represent the respiratory overflow volume provoked by acetylcholine as a percentage of the maximal overflow volume (100%) obtained by totally occluding the tracheal cannula. In some experiments, airway reactivity was expressed by the area under the dose-response curve (AUC) of bronchoconstriction against the acetylcholine concentration.
Examination of bronchoalveolar lavage fluid (BALF)
Immediately after the measurement of airway reactivity to
acetylcholine, BALF was collected by lavaging whole-lung three times
with 0.7-ml aliquots of physiological saline containing 0.1% BSA via
the tracheal cannula while gently massaging the thorax. The BALF
recovered from one mouse was pooled, centrifuged, and the cells were
resuspended in 100 µl saline containing 0.1% BSA. Cell numbers were
determined using a hemocytometer and 5 x
104 cells were cytocentrifuged onto a glass
slide. Cells were stained with Diff-Quik (International Reagent, Kobe,
Japan), and cell types were identified by morphological criteria. Two
hundred cells were examined per slide for differential count.
Concentration of cytokines in BALF was determined by ELISA. ELISA kits
from R&D Systems (Minneapolis, MN) were employed for the measurement of
IL-4, IL-12 p70, and IFN-
, and a kit from Endogen (Woburn, MA) was
employed for the measurement of IL-5.
Reconstitution of mast cells
Reconstitution of mast cells in W/Wv mice was conducted by the method described by Kung et al. (17) with a slight modification. Bone marrow cells of +/+ mice were seeded in RPMI 1640 medium (Life Technologies, Rockville, MD) supplemented with 10 ng/ml recombinant murine IL-3 (Kirin Brewery, Tokyo, Japan), 10% FCS, 2 mM glutamine, 50 U/ml penicillin, and 100 µg/ml streptomycin at a concentration of 5 x 105 nucleated cells/ml and cultured at 37°C in a humidified atmosphere of 5% CO2 and 95% air. Culture medium was replaced every 7 days. After 5 wk of culture, cells were harvested and suspended in PBS. Staining of the cells with May-Grünwald-Giemsa solution indicated that nearly 99% of viable cells were mast cells and the remainder macrophage-like cells or neutrophilic cells. No stem cell-like cell was detected in the mast cell preparation. A total of 2 x 107 bone marrow-derived mast cells was injected i.v. into each W/Wv mouse through a tail vein. Four weeks later, the reconstituted mice were immunized with alum-adsorbed OVA by the method described.
Determination of IgE and IgG1 Abs
Mouse sera were obtained 20 days after primary immunization and anti-OVA IgE and IgG1 Abs in the sera were measured by ELISA. The methods for the measurement of IgE and IgG1 Abs were essentially the same as those described by Tomura et al. (18). Briefly, microtiter plates were coated with 3 µg/ml of monoclonal anti-mouse IgE. After blocking with Superblock (Pierce, Rockford, IL) and washing with TBST, appropriate dilutions of serum samples in TBST containing 1% BSA were added to the plate. IgE Abs bound to the plates were determined using biotinylated OVA, alkaline phosphatase-streptavidin conjugate (Zymed, San Francisco, CA), and alkaline phosphatase colormerizing kit (AMPAK; Dako Japan, Kyoto, Japan). The IgG1 Abs bound to the plates, coated with 20 µg/ml OVA, were quantitated by ELISA using alkaline phosphatase-coupled rabbit anti-mouse IgG1 and phosphatase substrate system (Kirkegaard & Perry Laboratories, Gaithersburg, MD). The IgE and IgG1 Ab titers in the samples were related to a pooled serum standard containing 112 µg/ml of IgG1 anti-OVA Abs and 762 ng/ml of IgE anti-OVA Abs in 100,000 units.
Histological studies
Lungs were fixed with 10% Formalin, and the tissues were embedded in paraffin. Sections (5 µm) were stained with hematoxylin and eosin for light microscopic examinations. To examine the presence and distribution of tissue mast cells, lung tissues were fixed in Carnoy’s fixative and sections were stained with toluidine blue (19).
Statistical analysis
Homogeneity of variance was tested by the F test. Student’s t test was applied in cases in which the variance was homogeneous, whereas the Aspin-Welch’s test was applied when the variance was heterogeneous. A p value of <0.05 was considered to be significant. Values for all measurements were expressed as means ± SE.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Experiments were conducted to establish a mouse model of
developing AHR. BALB/c mice were immunized with alum-adsorbed OVA and
exposed to OVA aerosol. Determination of airway reactivity to
acetylcholine indicated that the mice immunized with OVA demonstrated a
marked bronchoconstriction in response to 0.5–1 mg/kg of
acetylcholine, whereas the airway of unimmunized control mice barely
responded to the same doses (Fig. 1
a). It was also found that
the mice immunized with alum-adsorbed OVA but received saline
inhalation exhibited the airway reactivity comparable to that observed
in unimmunized but OVA-aerosolized mice (results not shown). As
expected, sera of the immunized and OVA-challenged mice contained a
substantial concentration of both IgE (18759 ± 3648.1 U) and IgG1
(16918.5 ± 1214 U) anti-OVA Abs, but neither of the Abs was
detectable in the sera of unimmunized control mice.
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b). It was also found that BALF of the
immunized mice contained both IL-4 (17.42 ± 4.44 pg/ml) and IL-5
(121.75 ± 24.19 pg/ml). Neither IL-12 nor IFN- was detected in
BALF from the immunized and unimmunized mice.
In view of accumulated evidence for the involvement of eosinophils in
allergic inflammation, which may cause AHR (1, 2, 3, 20, 21),
we determined the possible effects of anti-IL-5 mAb in suppressing
the development of allergic inflammation and AHR in aerosolized mice.
Three groups of BALB/c mice were immunized with OVA and then challenged
three times with aerosolized OVA. Two groups of the immunized mice
received i.p. injections of either 3 µg or 30 µg of anti-IL-5
two hours before each OVA challenge, whereas the third group received
i.p. injections of 30 µg of irrelevant rat IgG1 as a control. As
expected from the previous observations of Corry et al.
(8), administration of 30 µg of anti-IL-5 resulted
in marked reduction in eosinophil number in BALF (Fig. 2a). Results of histological
examination of lung tissues paralleled the number of eosinophils in
BALF. In control mice, which received the irrelevant Ab, a large number
of eosinophils were found in the peribronchial regions of the lung, but
infiltration of eosinophils into the regions was markedly suppressed by
the injections of 30 µg of anti-IL-5. Despite the reduction in
eosinophil numbers in BALF and lung tissues to about 10%, airway
reactivity to acetylcholine in the anti-IL-5-treated mice was not
significantly different from that of the control animals which received
irrelevant Ab (Fig. 2b). These results indicated that in our
murine model, some cellular responses other than infiltration of
eosinophils may play a critical role in the development of
AHR.
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To determine possible roles of mast cells in the development of
Ag-induced AHR, comparisons were made between mast cell-deficient
W/Wv mice and congenic littermates (+/+ mice).
They were immunized with alum-adsorbed OVA and challenged with
aerosolized OVA three times, following exactly the same protocol
employed for BALB/c mice. Measurement of IgE and IgG1 anti-OVA Abs
in the sera of the immunized mice, taken at day 20, showed no
significant difference between the W/Wv and +/+
mice in the Ab responses (Fig. 3a). However, determination of
airway reactivity to acetylcholine showed a clear difference between
the two strains. As shown in Fig. 3b, immunization and
challenges with aerosolized OVA induced AHR to acetylcholine in +/+
mice but failed to generate AHR in W/Wv mice. The
results were confirmed by measuring the AUC of bronchoconstriction.
Although the airway of W/Wv mice gave a weak
response to 4 mg/kg of acetylcholine, no significant difference was
observed in the AUC between immunized and unimmunized groups of
W/Wv mice. As expected, there was a significant
difference (p < 0.05) in the AUC between the
immunized groups of the two strains. However, the bronchoprovocation
with aerosolized OVA appears to induce allergic inflammation in the
OVA-primed W/Wv mice. Examination of nucleated
cells in the BALF of the mast cell-deficient mice showed a marked
increase in eosinophils, comparable in extent to that observed in
aerosolized +/+ mice (Fig. 4a). Histological
examination of lung tissues showed that infiltration of eosinophils in
peribronchial tissues in the W/Wv mice was
comparable to that observed in +/+ mice. It was also found that BALF
from the two strains contained comparable concentrations of IL-4 and
IL-5 (Fig. 4b).
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). The number of mast cells in the lung
of mast cell-reconstituted W/Wv mice was about
one-half that of +/+ mice. As expected, IgE and IgG1 anti-OVA Abs
formed by the reconstituted animals were comparable to those of
W/Wv mice immunized with the same dose of
alum-adsorbed OVA. To determine the effect of mast cell reconstitution
on the development of AHR, seven mice, each of +/+,
W/Wv, and those reconstituted with mast cells
were immunized with OVA and then challenged three times with
aerosolized OVA. Determination of bronchoconstriction to acetylcholine,
shown in Fig. 6a, confirmed
that immunization and Ag challenge failed to induce AHR in
W/Wv mice; however, reconstitution with mast
cells restored the responsiveness of the airways. The extent of AHR to
acetylcholine in the reconstituted mice was comparable to that observed
in +/+ mice. Differences between AUC values in
W/Wv mice and those in the reconstituted mice
were statistically significant (Fig. 6a). Microscopic
examination of the BALF of W/Wv mice and the
reconstituted mice indicated that the presence of mast cells in the
lung did not affect the Ag-induced influx of eosinophils into the
airways (Fig. 6b).
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, determination of bronchoconstriction
to acetylcholine on day 21 clearly showed AHR in
W/Wv. Under the experimental conditions employed,
there was no significant difference between the
W/Wv and +/+ mice in the AUC. Histological
examination of lung tissues of the W/Wv mice
employed in the experiment confirmed the lack of mast cells. The
results indicated that AHR could be induced by frequent
bronchoprovocations in the mast cell-deficient mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Murine models for aeroantigen-induced eosinophilic inflammation and AHR
have been described by several investigators. One of the
characteristics of the present model is the proportion of cellular
components in BALF. When BALB/c mice were immunized and aerosol
challenged under the protocol described in Materials and
Methods, BALF contained 1.5–2.0 x 106
eosinophils, which represented nearly 80% of total BALF cells. Similar
results were obtained when +/+ mice were immunized and challenged with
aerosolized OVA by the same protocol (Fig. 4a). The
proportion of eosinophils in BALF may differ depending on mouse
strains, immunization regimen, and frequency of Ag challenge. Nagai et
al. (23) immunized BALB/c mice and +/+ mice with 50 µg
of alum-adsorbed OVA on days 0 and 12 and aerosolized three times with
OVA, but the number of eosinophils in BALF was in the order of
1–3 x 105, which comprised 40–50% of the
total cells in BALF. Similarly, Takeda et al. (22)
immunized +/+ mice with 20 µg of alum-adsorbed OVA on days 0 and 13
and challenged them three times with aerosolized OVA. The number of
eosinophils in BALF was 3 x 105, which
comprised 50% of the total cells. On the other hand, Corry et al.
(8) immunized BALB/c mice by four weekly injections of
alum-adsorbed OVA, gave two to three Ag challenges with a high
concentration of aerosolized OVA, and obtained 2 to 3 x
106 eosinophils in BALF. Thus, the major reason
for the predominance of eosinophils in BALF in our system appears to be
related to the immunization regimen. It has been believed that
eosinophils play a dominant role in allergic inflammation (1, 2, 3, 20, 21). In our system, however, the number of eosinophils in
BALF did not correlate with the development of AHR. Administration of
30 µg of anti-IL-5 mAb before each Ag challenge markedly
inhibited airway eosinophilia, but the treatment did not affect the
development of AHR (Fig. 2b). Similar results were reported
by Corry et al. (8) and Nagai et al. (23),
who have established murine models of AHR in BALB/c mice. The present
experiments also indicated that eosinophil infiltration in the airway
was comparable in BALB/c and +/+ mice when they were immunized and
challenged with aerosolized OVA under the same protocol (cf Fig. 1b vs Fig. 4a). However, bronchoconstriction
induced in BALB/c mice by 0.5–1 mg/kg acetylcholine was much more than
that observed in the +/+ mice (cf Fig. 1a vs Fig. 3b), indicating the lack of parallelism between AHR and
eosinophil infiltration depending on mouse strains.
An important finding obtained in the present experiments was clear
evidence for the role of mast cells in the development of Ag-induced
AHR. It was found that W/Wv and +/+ mice were
comparable in IgE and IgG1 Ab responses. After three times of
bronchoprovocation with OVA aerosol, +/+ mice showed AHR to
acetylcholine, whereas W/Wv mice failed to do so
(Figs. 3b and 6a). It is known that
W/Wv mice have several genetic defects, including
lack of mast cells (24). However, the present experiments
showed that reconstitution of W/Wv mice with +/+
mouse-derived cultured mast cells restored the capacity of developing
AHR, indicating that mast cells play an essential role in the
development of AHR in our system. Possibilities may be considered that
mast cell preparation transferred might be contaminated with
pluripotent hematopoietic stem cells which may have differentiated in
vivo. In our experiments, however, no stem cell-like cell was detected
in the mast cell suspension transferred. Since the mast cells were
obtained after a 5-wk culture of bone marrow cells in the presence of
IL-3 but in the absence of stem cell factor, it is quite unlikely that
pluripotent stem cells were maintained in the cultures and these cells,
rather than mast cells, were responsible for restoration of
AHR.
The findings obtained in the present experiments are in agreement with the predictions that mast cells are involved in the development of asthma. Martin et al. (25) have shown that in vivo activation of mast cells by an injection of anti-IgE into normal mice enhanced airway responsiveness to methacholine, as determined by pulmonary conductance. The effect of the anti-IgE pretreatment was not detectable in mast cell-deficient W/Wv mice; however, transfer of bone marrow-derived cultured mast cells from congenic mice into the mast cell-deficient mice restored the effect of the anti-lgE pretreatment on the enhanced pulmonary responses. It was also demonstrated by Oshiba et al. (26) that passive sensitization of BALB/c mice with monoclonal IgE anti-OVA Ab, followed by challenge of the mice with aerosolized OVA on 2 consecutive days resulted in eosinophil infiltration in peribronchial regions and an increase in the responsiveness of tracheal smooth muscle to electrical field stimulation. Since Ag-specific T cells were not primed in this system, the increased number of eosinophils in BALF is probably due to the formation of cytokines, such as IL-5, by mast cells. Kung et al. (17) also provided evidence that products from mast cells are involved in eosinophil infiltration in the airways. In our present experiment, in which actively immunized mice were challenged with OVA aerosol, however, no difference was found between W/Wv and +/+ mice in eosinophil influx into airways and in the concentration of IL-5 in BALF. The results strongly suggest that in our murine model, the major cell source of IL-5, which is involved in the recruitment of eosinophils into airways, is Th2 cells rather than mast cells. Marked eosinophilic response in W/Wv mice, which failed to develop AHR, also indicates that infiltration of eosinophils into the airways is not sufficient for the development of AHR. Previous studies suggested that eosinophil activation rather than accumulation in local tissues correlated with increased airway reactivity (27). One might speculate that some of the mast cell-derived mediator(s), such as platelet-activating factor (28, 29), may be involved in activation/degranulation of eosinophils. It has been predicted that mast cell-derived mediators such as platelet-activating factor (30, 31), leukotrienes (31, 32), thromboxane A2 (33), and tryptase (34, 35) have the capacity to increase airway reactivity. The present experiment indicating a clear difference between W/Wv and +/+ mice in the development of AHR suggests that some of the mast cell-derived mediators are involved in the development of AHR in our system.
Failure of W/Wv mice to develop AHR in our
present experiment appears to conflict with the findings by Takeda et
al. (22), who demonstrated no significant difference
between W/Wv and +/+ mice in the development of
Ag-induced AHR. However, the discrepancies are probably due to
differences in the immunization regimen for sensitization and the
protocol of bronchoprovocation employed in the two experiments. In our
experiment as well, AHR could be developed in
W/Wv mice by increasing the frequency and Ag dose
for bronchoprovocation (cf Fig. 7). It is obvious that under this
experimental condition, AHR could develop without participation of mast
cells.
Conflicting results have been reported on the possible role of IL-5/eosinophils and IgE in the development of AHR. Corry et al. (8) and Nagai et al. (23) as well as our present experiments clearly showed that administration of anti-IL-5, which blocked the Ag-induced release of eosinophils from bone marrow (36) and markedly diminished eosinophil infiltration in the lung, failed to affect the development of Ag-induced AHR. In these systems, there is no clear evidence that IL-5/eosinophils play a major role in the development of AHR. In contrast, Foster et al. (7) have shown that the IL-5 gene-deficient mice failed to develop AHR. Furthermore, Hogan et al. (37) claimed that immunization of IL-4-deficient mice with OVA and subsequent challenge with aerosolized OVA resulted in the development of AHR. Since the IL-4-deficient mice failed to form IgE or IgG1 Abs, these experiments indicated that AHR could be induced in the mouse without participation of the IgE/mast cell system. This idea is supported by more recent experiments by Lee et al. (38), who have generated transgenic mice which constitutively express IL-5 in the lung epithelium. The airway expression of IL-5 resulted in the accumulation of eosinophils in the peribronchial area, eosinophil infiltration of the airways, and development of AHR in the absence of aerosolized Ag challenge.
The most likely explanation for the conflicting results described above is that AHR could be induced by at least two distinct cellular mechanisms. One would go through the IgE-dependent activation of mast cells, which initiates a sequence of events that can induce AHR, whereas the other mechanism is an eosinophil- and IL-5-dependent process in which participation of IgE/mast cells is not required. A fundamental question remaining to be answered is which mechanism is predominant in human asthma, which is a syndrome caused by inflammation of the airways. In some asthmatic patients, AHR may be caused by the IL-5- and eosinophil-dependent mechanism alone. In typical allergic asthma, however, we suspect that both the IgE-dependent and IgE-independent activation events take place in concert, and the mast cell/IgE system probably plays a key role in the development of AHR.
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Footnotes |
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2 Abbreviations used in this paper: AHR, airway hyperresponsiveness; alum, aluminum hydroxide gel; BALF, bronchoalveolar lavage fluid; AUC, area under the dose-response curve.
Received for publication June 18, 1999. Accepted for publication December 23, 1999.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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D. D'Ambrosio, M. T. Cantorna, A. August, Y. Zhu, and M. Froicu Increased IgE but Reduced Th2-Type Inflammation in Vitamin D Receptor-Deficient Mice J. Immunol., April 15, 2005; 174(8): 4451 - 4451. [Full Text] [PDF]
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 H. Tanaka, M. Komai, K. Nagao, M. Ishizaki, D. Kajiwara, K. Takatsu, G. Delespesse, and H. Nagai Role of Interleukin-5 and Eosinophils in Allergen-Induced Airway Remodeling in Mice Am. J. Respir. Cell Mol. Biol., July 1, 2004; 31(1): 62 - 68. [Abstract] [Full Text] [PDF]
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H. Matsushima, N. Yamada, H. Matsue, and S. Shimada TLR3-, TLR7-, and TLR9-Mediated Production of Proinflammatory Cytokines and Chemokines from Murine Connective Tissue Type Skin-Derived Mast Cells but Not from Bone Marrow-Derived Mast Cells J. Immunol., July 1, 2004; 173(1): 531 - 541. [Abstract] [Full Text] [PDF]
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S. Ishii, T. Nagase, H. Shindou, H. Takizawa, Y. Ouchi, and T. Shimizu Platelet-Activating Factor Receptor Develops Airway Hyperresponsiveness Independently of Airway Inflammation in a Murine Asthma Model J. Immunol., June 1, 2004; 172(11): 7095 - 7102. [Abstract] [Full Text] [PDF]
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C. Taube, X. Wei, C. H. Swasey, A. Joetham, S. Zarini, T. Lively, K. Takeda, J. Loader, N. Miyahara, T. Kodama, et al. Mast Cells, Fc{epsilon}RI, and IL-13 Are Required for Development of Airway Hyperresponsiveness after Aerosolized Allergen Exposure in the Absence of Adjuvant J. Immunol., May 15, 2004; 172(10): 6398 - 6406. [Abstract] [Full Text] [PDF]
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D. C. Cara, K. V. J. Ebbert, and D.-M. McCafferty Mast Cell-Independent Mechanisms of Immediate Hypersensitivity: A Role for Platelets J. Immunol., April 15, 2004; 172(8): 4964 - 4971. [Abstract] [Full Text] [PDF]
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 M. A. Aronica, S. McCarthy, S. Swaidani, D. Mitchell, M. Goral, J. R. Sheller, and M. Boothby Recall Helper T Cell Response: T Helper 1 Cell-resistant Allergic Susceptibility without Biasing Uncommitted CD4 T Cells Am. J. Respir. Crit. Care Med., March 1, 2004; 169(5): 587 - 595. [Abstract] [Full Text] [PDF]
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R. K. Ikeda, M. Miller, J. Nayar, L. Walker, J. Y. Cho, K. McElwain, S. McElwain, E. Raz, and D. H. Broide Accumulation of Peribronchial Mast Cells in a Mouse Model of Ovalbumin Allergen Induced Chronic Airway Inflammation: Modulation by Immunostimulatory DNA Sequences J. Immunol., November 1, 2003; 171(9): 4860 - 4867. [Abstract] [Full Text] [PDF]
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C.-K. Yu and C.-L. Chen Activation of Mast Cells Is Essential for Development of House Dust Mite Dermatophagoides farinae-Induced Allergic Airway Inflammation in Mice J. Immunol., October 1, 2003; 171(7): 3808 - 3815. [Abstract] [Full Text] [PDF]
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 N. Yamamoto, K. Takeshita, M. Shichijo, T. Kokubo, M. Sato, K. Nakashima, M. Ishimori, H. Nagai, Y.-F. Li, T. Yura, et al. The Orally Available Spleen Tyrosine Kinase Inhibitor 2-[7-(3,4-Dimethoxyphenyl)-imidazo[1,2-c]pyrimidin-5-ylamino]nicotinamide Dihydrochloride (BAY 61-3606) Blocks Antigen-Induced Airway Inflammation in Rodents J. Pharmacol. Exp. Ther., September 1, 2003; 306(3): 1174 - 1181. [Abstract] [Full Text] [PDF]
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V. Lam, J. Kalesnikoff, C. W. K. Lee, V. Hernandez-Hansen, B. S. Wilson, J. M. Oliver, and G. Krystal IgE alone stimulates mast cell adhesion to fibronectin via pathways similar to those used by IgE + antigen but distinct from those used by Steel factor Blood, August 15, 2003; 102(4): 1405 - 1413. [Abstract] [Full Text] [PDF]
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C. D. Chung, F. Kuo, J. Kumer, A. S. Motani, C. E. Lawrence, W. R. Henderson Jr., and C. Venkataraman CCR8 Is Not Essential for the Development of Inflammation in a Mouse Model of Allergic Airway Disease J. Immunol., January 1, 2003; 170(1): 581 - 587. [Abstract] [Full Text] [PDF]
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S. M. Drouin, D. B. Corry, T. J. Hollman, J. Kildsgaard, and R. A. Wetsel Absence of the Complement Anaphylatoxin C3a Receptor Suppresses Th2 Effector Functions in a Murine Model of Pulmonary Allergy J. Immunol., November 15, 2002; 169(10): 5926 - 5933. [Abstract] [Full Text] [PDF]
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 M. E. Viana, N. H. Coates, S. H. Gavett, M. K. Selgrade, S. J. Vesper, and M. D. W. Ward An Extract of Stachybotrys chartarum Causes Allergic Asthma-like Responses in a BALB/c Mouse Model Toxicol. Sci., November 1, 2002; 70(1): 98 - 109. [Abstract] [Full Text] [PDF]
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A. Masuda, Y. Yoshikai, K. Aiba, and T. Matsuguchi Th2 Cytokine Production from Mast Cells Is Directly Induced by Lipopolysaccharide and Distinctly Regulated by c-Jun N-Terminal Kinase and p38 Pathways J. Immunol., October 1, 2002; 169(7): 3801 - 3810. [Abstract] [Full Text] [PDF]
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G. Path, A. Braun, N. Meents, S. Kerzel, D. Quarcoo, U. Raap, G. W. Hoyle, W. A. Nockher, and H. Renz Augmentation of Allergic Early-Phase Reaction by Nerve Growth Factor Am. J. Respir. Crit. Care Med., September 15, 2002; 166(6): 818 - 826. [Abstract] [Full Text]
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S. I. Mayr, R. I. Zuberi, M. Zhang, J. de Sousa-Hitzler, K. Ngo, Y. Kuwabara, L. Yu, W.-P. Fung-Leung, and F.-T. Liu IgE-Dependent Mast Cell Activation Potentiates Airway Responses in Murine Asthma Models J. Immunol., August 15, 2002; 169(4): 2061 - 2068. [Abstract] [Full Text] [PDF]
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J. R. Crosby, G. Cieslewicz, M. Borchers, E. Hines, P. Carrigan, J. J. Lee, and N. A. Lee Early Phase Bronchoconstriction in the Mouse Requires Allergen-Specific IgG J. Immunol., April 15, 2002; 168(8): 4050 - 4054. [Abstract] [Full Text] [PDF]
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A. A. Humbles, B. Lu, D. S. Friend, S. Okinaga, J. Lora, A. Al-garawi, T. R. Martin, N. P. Gerard, and C. Gerard The murine CCR3 receptor regulates both the role of eosinophils and mast cells in allergen-induced airway inflammation and hyperresponsiveness PNAS, February 5, 2002; 99(3): 1479 - 1484. [Abstract] [Full Text] [PDF]
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R. Venkayya, M. Lam, M. Willkom, G. Grunig, D. B. Corry, and D. J. Erle The Th2 Lymphocyte Products IL-4 and IL-13 Rapidly Induce Airway Hyperresponsiveness Through Direct Effects on Resident Airway Cells Am. J. Respir. Cell Mol. Biol., February 1, 2002; 26(2): 202 - 208. [Abstract] [Full Text] [PDF]
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D. T. Deurloo, B. C.A.M. van Esch, C. L. Hofstra, F. P. Nijkamp, and A. J.M. van Oosterhout CTLA4-IgG Reverses Asthma Manifestations in a Mild but Not in a More ""Severe"" Ongoing Murine Model Am. J. Respir. Cell Mol. Biol., December 1, 2001; 25(6): 751 - 760. [Abstract] [Full Text] [PDF]
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 S. Page, A. J. Ammit, J. L. Black, and C. L. Armour Human mast cell and airway smooth muscle cell interactions: implications for asthma Am J Physiol Lung Cell Mol Physiol, December 1, 2001; 281(6): L1313 - L1323. [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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 C. M.M. Williams and S. J. Galli Mast Cells Can Amplify Airway Reactivity and Features of Chronic Inflammation in an Asthma Model in Mice J. Exp. Med., August 7, 2000; 192(3): 455 - 462. [Abstract] [Full Text] [PDF]
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