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Division of Biochemistry and Molecular Biology, The John Curtin School of Medical Research, Australian National University, Canberra, Australia
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Introduction |
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The immunomodulatory functions of IL-4 and IL-5 have identified these cytokines as key therapeutic targets for the relief of airways inflammation and obstruction in asthma. There is, however, opposing evidence as to the comparative significance of each cytokine in the mechanisms underlying the induction of airways hyperreactivity (25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35). In particular, airways eosinophilia, which is regulated by IL-5, is not always implicated in the development of airways hyperreactivity in asthma or in animal models of this disease (15, 27, 28, 29, 30, 32, 33, 34, 35). Recently, mouse models of allergic airways inflammation have been used to provide insights into the potential contribution of individual inflammatory cells and molecules to the pathogenesis of asthma. In IL-5-deficient (IL-5-/-)3 mice of the C57BL/6 strain, we have demonstrated an obligatory role for this cytokine in the induction of eosinophilia, in morphologic changes to the airways, and in the development of airways hyperreactivity to ß-methacholine in response to aeroallergen challenge (25). IL-5 and associated eosinophilia were also shown to regulate the induction of airways hyperreactivity during allergic inflammation in IL-4-/- mice (129Sv x C57BL/6 background) (26). Our investigations support the hypothesis that increased levels of eosinophils and their products in the lung underlie pathologic changes to the airways and enhanced bronchial reactivity in asthma (5, 8, 9, 10, 11, 12, 13). In marked contrast, an essential role for IL-4 and not IL-5 or eosinophils in the development of aeroallergen-induced airways hyperreactivity was observed by Corry et al. in BALB/c mice treated with inhibitory mAbs to these cytokines (27). Significantly, airways hyperreactivity was reduced but not abolished by anti-IL-4 mAb treatment (27). Furthermore, antagonism of leukotriene function in BALB/c mice inhibited the accumulation of mucus and eosinophils in the airways but did not attenuate airways hyperreactivity in response to aeroallergen challenge (34). Similar investigations in BALB/c mice and other strains have also suggested that IgE in association with airways eosinophilia is required for the induction of enhanced airways reactivity to spasmogens (28, 31, 35).
The innate contributions of IL-4, IL-5, and the effector pathways of eosinophils and mast cells to the induction of airways hyperreactivity in various strains of mice, in conjunction with different sensitization protocols, have been postulated to explain the apparent discordant observations described above (36). C57BL/6 mice are genetically deficient in some mast cell-derived inflammatory mediators, which could make this strain resistant to mast cell-mediated airways hyperreactivity (37). In contrast to C57BL/6 mice, BALB/c mice produce high levels of IL-4 and IgE in response to sensitization (27). Thus, airways hyperreactivity has been proposed to be predominantly regulated by IgE-mediated activation of mast cells in BALB/c mice and solely regulated by an IL-5-eosinophil-dependent mechanism in C57BL/6 mice (36). However, this hypothesis does not explain why eosinophils recruited to the airways in response to allergen inhalation in BALB/c mice do not become activated and thus contribute through the release of inflammatory mediators to the induction of airways hyperreactivity. An alternative hypothesis is that the contribution of eosinophils to the development of airways hyperreactivity in BALB/c mice may be masked by the coexistence of a pathway(s) that operates independently of this leukocyte.
The aim of this investigation was to ascertain whether multiple physiologic pathways predispose to aeroallergen-induced airways hyperreactivity in BALB/c mice. In this investigation, we have employed IL-4-/- and IL-5-/- mice of the BALB/c strain, in combination with inhibitory mAbs for these cytokines, in an attempt to unequivocally dissect the contribution of these factors and eosinophils to the development of airways hyperreactivity during allergic inflammation. Subcutaneous (27) and intraperitoneal (25) sensitization protocols were also compared to determine whether the route of Ag administration affects the contribution of inflammatory cells and cytokines to pathophysiologic features of the inflammatory response. Aeroallergen-induced airways hyperreactivity was shown to be present in IL-5-/- or IL-4-/- mice even when these mice were additionally treated with anti-IL-4- or anti-IL-5- mAbs. However, IL-5 and airways eosinophilia were essential for the development of morphologic changes to the airways. Thus, airways hyperreactivity persisted in the absence of pronounced airways inflammation and gross structural changes to the respiratory epithelium, but was ablated by anti-CD4+ mAb. Our data indicate that CD4+ T cells operate at least two pathways that can act independently to induce airways hyperreactivity in BALB/c mice. The coexistence of parallel pathways may account for the dissociation of airways eosinophilia from the development of airways hyperreactivity in some cases of asthma and in models of this disease in BALB/c mice and may have important implications for the treatment of asthma.
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Materials and Methods |
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BALB/c IL-4-/- mice (provided by Dr.N. Noben-Trauth, National Institutes of Health (38)) or IL-5-/- mice (BALB/c 8th–10th generation derived from IL-5-/- C57BL/6 (24)), 6 to 10 wk of age, were sensitized by i.p. injection with 50 µg OVA/1 mg Alhydrogel (Commonwealth Serum Laboratories (CSL), Parkville, Australia) in 0.9% sterile saline on days 0 and 12. Nonsensitized mice received 1 mg of Alhydrogel in 0.9% saline. On day 24, the appropriate groups of mice were aeroallergen challenged with OVA (nonsensitized mice received saline only) as previously described (25, 26). Twenty-four hours after the last aeroallergen challenge, airways hyperreactivity was measured, or mice were sacrificed by cervical dislocation and their airways characterized for inflammatory infiltrates and morphologic changes. Lung responses of IL-4-/- mice or IL-5-/- mice were compared with wild-type mice, which were simultaneously treated. In some experiments, wild-type mice received 1 mg Alhydrogel in 0.9% saline on day 0 and 12 and were than aeroallergen challenged with OVA. To determine whether the dose, route, and frequency of allergen challenge affected the contribution of IL-5 and eosinophils to the induction of allergic airways disease, mice were also s.c. injected with a lower dose of OVA (25 µg/1 mg Alhydrogel) weekly for 4 wk and subsequently aeroallergen challenged (three times daily at 5-day intervals) as described by Corry et al. (these investigators had previously reported no role for eosinophils in the development of airways hyperreactivity by using this model (27)). Mice were treated according to Australian National University Animal Welfare guidelines and were housed in a specific pathogen-free facility.
Pretreatment of mice with anti-IL-4, anti-IL-5, or anti-CD4 mAbs
IL-5-/- mice were injected i.p. with anti-IL-4 mAb (1 mg of 11B11) 24 h before i.p. injections with OVA and then weekly throughout the experimental protocol. IL-4-/- mice were injected i.p. with anti-IL-5 mAb (2 mg, TRFK-5) on days 23 and 27. Anti-CD4 mAb (0.75 mg of GK1.5) was administered before aeroallergen challenge on day 23 and on days 26 and 29. Mice also received the appropriate concentration of isotype control Ab (ßGL113). All Abs were administered in sterile saline.
Characterization of lung morphology and leukocytes in blood, tissue, and bronchoalveolar lavage fluid (BALF)
Lung tissue representing the central (bronchi-bronchiole) and peripheral (alveoli) airways were fixed in 10% phosphate-buffered formalin, sectioned, and stained with May-Grunwald-Giemsa solution or hematoxylin-eosin. Leukocytes in the blood, BALF, and lung were identified by morphologic criteria and quantified as previously described (25).
Measurement of airways hyperreactivity
Airways hyperreactivity was measured with a bronchospasm transducer (Ugo Basil 7020), which was coupled to a Lab Mac/8 analysis station (AdInstruments, Sydney, Australia) as previously described (25, 26). Changes in respiratory overflow volume were determined during cumulative i.v. administration of ß-methacholine. The increase in respiratory overflow volume provoked by ß-methacholine is represented as a percentage of the maximal overflow volume (100%) obtained by totally occluding the tracheal cannula. The concentration that induced a maximal response in OVA-sensitized and aerosolized wild-type mice is shown for all other groups.
Preparation of whole lung homogenates
Homogenates were prepared after cannulating the trachea and perfusing the airways with a 1-ml solution of 1% collagenase/PBS at 4°C. The lungs were then removed, resuspended in HBSS/10% FCS, and vigorously vortexed before being incubated at 37°C for 30 min. The resulting cell suspension was homogenized and filtered through nylon mesh (70 µM) and centrifuged at 500 x g for 5 min at 4°C. The resulting pellet was then resuspended in MLC/10% FCS, filtered through FACS gauze, and centrifuged at 500 x g for 5 min at 4°C. Cells were then resuspended in MLC/10% FCS and used for OVA or anti-CD3 stimulation assays.
IL-5 production by T cells in cultures of whole lung homogenates after stimulation with OVA or anti-CD3
Lung homogenates were cultured (2 x 106 cells/well) in MLC/10% FCS on OVA (50 µg/well) or anti-CD3 (5 µg/ml)-coated U-bottom 96-well plates (100 µl/well) for 72 h (26). Cell-free culture supernatants were then collected and stored in aliquots at -70°C until IL-5 levels were determined.
Measurement of IL-5 levels in culture supernatants
IL-5 concentrations were determined in the supernatants from OVA (50 µg/ml)- or anti-CD3 (5 µg/ml)-stimulated lung cell homogenates (26). Briefly, 96-well round-bottom immunoassay plates were coated with rat anti-mouse IL-5 mAb (5 µg/ml; clone TRFK-5). Plates were blocked with 5% FCS/PBS for 1 h and incubated with serial dilutions of cultured supernatants or standard murine IL-5 at 37°C. Murine IL-5 was detected with biotinylated rat anti-mouse IL-5 (3 µg/ml; TRFK-4). Plates were incubated with streptavidin-conjugated peroxidase (Jackson Immunoresearch Laboratories, West Grove, PA) for 1 h at 37°C, washed, and ABTS substrate solution (Kirkegaard and Perry Laboratories, Gaithersburg, MD) was added. After an appropriate incubation time, the reaction was stopped with 0.1 M SDS solution. Plates were read in a microplate reader (Bio-Tek Instruments, Winooski, VT) at 490 nm with reference to 405 nm. The sensitivity of the ELISA system was 0.5 ng/ml of IL-5.
Detection of major basic protein in the BALF
BALF was centrifuged (350 x g 4°C) for 5 min. Aliquots of the supernatant were removed and stored at -70°C until determined by immunoblot analysis. Dot blots were performed at room temperature using polyvinylidene difluoride (PVDF) membranes (Schleicher and Schuell, Dassel, Germany) that had been presoaked in 100% methanol for 1 min and then incubated in TBS solution (20 mM Tris-HCl, pH 7.5/150 mM NaCl) for 2 min. BALF samples were serially diluted (initial dilution, 1:2) in TBS solution and applied to the PVDF membranes. PVDF membranes were then air dried and washed with 100% methanol for 1 min and immersed in TBS solution for 4 min. Membranes were then blocked with 1% BSA/TBST solution (1% blot-qualified BSA/20 mM Tris-HCl, pH 7.5/150 mM NaCl/0.05% Tween 20) for 20 min, washed with TBST solution, and incubated with rabbit anti-mouse-major basic protein (MBP) Ab in TBST solution (1:2000) for 1 h. Membranes were then washed with TBST solution for 5 min and incubated with alkaline phosphatase-conjugated goat anti-rabbit Ig (Sigma, St. Louis, MO) for 45 min. Finally, membranes were washed with TBST solution and incubated with Western blue-stabilized substrate (Promega, Madison, WI). Reactions were stopped with deionized water when bands of interest had reached the desired intensity.
Determination of OVA-specific Ab titers by ELISA
OVA-specific Abs were detected in the sera from OVA-treated mice as previously described (26).
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Results |
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Aeroallergen challenge of OVA-sensitized wild-type mice resulted
in an increase in lymphocyte, neutrophil, macrophage, and eosinophil
numbers in the BALF (Fig. 1
A)
in comparison with mice treated with saline and aerosolized with saline
or OVA (Fig. 1A). In saline-immunized mice, no significant
differences in inflammatory cell numbers were observed between saline-
or OVA-aerosolized treatments (results for individual cell
populations x 104/ml of BALF for saline-immunized and
saline- or OVA-aerosolized treatment, respectively, are: lymphocytes,
0.84 ± 0.10 vs 0.97 ± 0.13; eosinophils not detected;
neutrophils, 0.35 ± 0.09 vs 0.51 ± 0.10; macrophages,
1.84 ± 0.5 vs 3.5 ± 0.7; n = 5).
Furthermore, there was no significant change in airways responsiveness
to ß-methacholine in these two groups. Percentage of maximal airways
occlusion for saline-immunized and saline- or OVA-aerosolized treatment
was 20 ± 0.5 vs 21.4 ± 7.0, respectively (n
= 5). Data are shown for a dose of 75 µg/kg ß-methacholine, which
induces a maximal response in wild-type mice. The composition of
individual leukocyte populations in the BALF were not significantly
different between mice that had been sensitized i.p. or s.c. with OVA
(Fig. 1A). Aeroallergen-induced recruitment of inflammatory
cells to the airways in both i.p. and s.c. injected OVA models
correlated directly with the development of a pronounced blood
eosinophilia (results not shown) and with enhanced airways reactivity
to ß-methacholine (Fig. 2). MBP was
also detected at similar levels in the BALF taken from both
sensitization models (Table I). These
results indicate that variations in sensitization and aeroallergen
challenge protocols did not significantly effect the development of the
inflammatory response or eosinophil activation in the lung or the
subsequent induction of airways hyperreactivity in wild-type mice.
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A), the inflammatory
response was significantly attenuated in IL-5-/- mice
(Fig. 1B). Aeroallergen challenge of IL-5-/-
mice did not induce a pronounced airways or blood eosinophilia (result
not shown), and the total numbers of individual leukocytes (neutrophil,
lymphocyte, or macrophages) in the BALF were significantly diminished
(Fig. 1, A and B). However, no significant
differences in the composition of individual leukocyte populations in
the BALF were observed between i.p. or s.c. OVA-sensitized
IL-5-/- mice. OVA-specific IgE and IgG1 were also
detected at similar levels in the sera of wild-type and
IL-5-/- mice that received OVA i.p. (Fig. 3) or s.c. (result not shown) injection.
Notably, in the absence of eosinophilia, airways hyperreactivity to
ß-methacholine in BALB/c mice was not abolished as previously
described in IL-5-/- C57BL/6 mice (25). Furthermore,
airways hyperreactivity was only slightly attenuated in
IL-5-/- mice that had been sensitized by i.p. injection
and not detectably affected in mice sensitized by the s.c. route (Fig. 2). These results support previous findings that aeroallergen-induced
airways hyperreactivity can occur independently of IL-5 and
eosinophilia in BALB/c mice, in contrast to our results in other
strains (25, 26, 27, 34). Furthermore, this observation did not appear to
be explained by variations in the sensitization or aeroallergen
challenge protocol employed.
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B). Lung tissue
after Ag inhalation was characterized by marked alterations in the
morphologic integrity of the airway walls (bronchi and broncheoli),
epithelial cell shedding, increased tissue cellularity, and extensive
mucosal edema. Eosinophils and particulates were also observed in the
airways lumina (Fig. 4B). In marked contrast to wild-type
mice exposed to OVA, minimal morphologic changes to airways structure
were observed in sensitized (i.p. or s.c.; results shown for i.p. only)
IL-5-/- mice (Fig. 4C). Furthermore, MBP was
detected only at background levels in cell-free BALF taken from
sensitized and aeroallergen-challenged IL-5-/- mice. In
saline-treated mice, MBP was not detected in cell-free BALF by
immunoblot analysis (Table I). Thus, allergen-induced morphologic
changes to the respiratory epithelium directly correlated with the
presence of activated airways eosinophils secreting MBP in both
sensitization models. However, the contribution of IL-5 and eosinophils
to the development of airways hyperreactivity was observed only in mice
sensitized by i.p. injection, and even in this case it was a minor
contribution. These results suggest that an alternative mechanism not
involving eosinophils can regulate airways hyperreactivity in BALB/c
mice and that this pathway predominates in mice sensitized by s.c.
injection.
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We next determined the contribution of IL-4-regulated Th2
inflammatory responses to aeroallergen-induced airways hyperreactivity.
As IL-5-independent airways hyperreactivity occurred in both
sensitization models and there were no differences in inflammatory cell
profiles between these groups, we investigated the role of IL-4 only in
the i.p. sensitization model. OVA aerosolization of i.p. sensitized
IL-4-/- mice resulted in a significant reduction in the
number of BALF eosinophils, lymphocytes (Fig. 1C),
neutrophils, and macrophages in comparison with wild-type mice (Fig. 1A). However, the numbers of cells in individual leukocyte
populations in the BALF were significantly increased in comparison with
mice treated with saline (Fig. 1C). Notably, eosinophil
numbers in the BALF of OVA-treated IL-4-/- mice
(3.15 x 104 ± 0.87, n = 6) (Fig. 1C) were significantly elevated in comparison with
OVA-treated IL-5-/- mice (0.0625 x 104
± 0.02, n = 6) (Fig. 1B), and MBP was
detected at similar intensities in BALF from sensitized and
aeroallergen-challenged wild-type and IL-4-/- mice (Table I). Furthermore, marked alterations in the morphologic integrity of the
airways occurred in sensitized IL-4-/- mice (Fig. 4).
IL-4-/- mice could also mount a pronounced blood and
peribronchial eosinophilia that was not significantly different between
aeroallergen-challenged wild-type and IL-4-/- mice
(results not shown), as previously described in 129Sv x C57BL/6
mice deficient in this factor (26). Moreover, aeroallergen-induced
morphologic changes to the airways (Fig. 4D) and airways
hyperreactivity (Fig. 2) were not attenuated in IL-4-/-
mice and were observed in the absence of OVA-specific IgE and in the
presence of reduced levels of IgG1 (Fig. 3, A and
B). These results indicate that in BALB/c mice, IL-4 is not
obligatorily involved in the generation of aeroallergen-induced airways
hyperreactivity or lung damage.
T cell production of IL-5 in IL-4-/- mice
In other mouse strains, we have demonstrated that airways
eosinophilia and hyperreactivity can be regulated by pathways that
operate independently of IL-4 but that are intimately associated with
IL-5 production by CD4+ T cells (26). In the present
investigation, stimulation of T cells with anti-CD3 or OVA in
homogenates of lungs taken from aeroallergen challenged
IL-4-/- BALB/c mice resulted in significant production of
IL-5 (albeit less than that observed with preparations from wild-type
mice; results not shown) in comparison with nonsensitized controls
(Fig. 5). These results suggest that in
IL-4-/- BALB/c mice, there are IL-5-secreting
CD4+ T cells present that, judging from results with other
mouse strains, have the potential to regulate aeroallergen-induced
airways hyperreactivity and pathologic changes to the lung.
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To determine the role of IL-5 and eosinophils in the induction of
airways hyperreactivity and lung damage that occurred independently of
IL-4, anti-IL-5 mAb was administered to IL-4-/- mice
before aeroallergen challenge. Aeroallergen challenge of mice
pretreated with anti-IL-5 mAb induced no airways (Fig. 6A) or blood (result not
shown) eosinophilia and minimal morphologic changes to airways
structure (result not shown; similar to that observed in
IL-5-/- mice (Fig. 4C)). However, airways
hyperreactivity to ß-methacholine was not attenuated in the absence
of IL-5 and eosinophilia in aeroallergen-challenged
IL-4-/- mice (Fig. 6B). Administration of
isotype control Ab did not affect eosinophilia or airways responses to
ß-methacholine (Fig. 6). To determine whether the total absence of
IL-5 was required in the BALB/c strain to inhibit airways
hyperreactivity, IL-5-/- mice were also treated with
anti-IL-4 mAb during periods of both systemic sensitization and
aerosolization. Pretreatment of IL-5-/- mice with
anti-IL-4-mAb inhibited the production of OVA-specific IgE (results
not shown) but failed to further attenuate aeroallergen-induced airways
hyperreactivity (Fig. 6B). In contrast, treatment of
IL-4-/- mice with anti-IL-5 mAb and anti-CD4 mAb
(or anti-CD4 mAb alone; result not shown) significantly reduced
lymphocyte numbers (but not neutrophil or macrophage numbers; result
not shown) in the BALF and abolished airways hyperreactivity (Fig. 6, A and B). The histologic sections of the lungs of
these mice resembled those of saline-treated mice, but in some regions
adjacent to the airways, foci of lymphocyte clusters were observed.
Collectively, these data indicate that there is another pathway
regulating aeroallergen-induced airways hyperreactivity in BALB/c mice
that is not dependent on IL-4 or IL-5 and that this pathway does not
result in the morphologic changes to the lungs that are produced by the
IL-5/eosinophil pathway in all strains of mice tested thus far.
Furthermore, the data demonstrate that CD4+ T cells play a
pivotal role in the activation of both pathways.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). This conclusion is supported by recent
investigations in anti-IL-5 mAb-treated BALB/c mice that were
sensitized i.p. or exclusively via the airways were a component of
airways hyperreactivity was also shown to be dependent on IL-5 and
eosinophil infiltration of the submucosal tissue (39, 40). Variations in the strain and/or mode of sensitization and severity of aeroallergen challenge have been proposed to account for the discordant observations on the role of IL-5-regulated eosinophilia in the induction of airways hyperreactivity in mice (36). In our current investigation, the degree of allergic inflammation and airways hyperreactivity was not altered by changing the route of sensitization (i.p. to s.c.) and aeroallergen challenge protocol. Furthermore, both of these sensitization protocols induced eosinophil activation and the release of MBP into the BALF, which directly correlated with pathologic changes to the airways. Thus, in the BALB/c strain, the complete contribution of IL-5 and eosinophils to the induction of airways hyperreactivity is likely to have been masked by the presence of another aeroallergen-activated pathway(s) that operates in parallel and independently of this leukocyte. Interestingly, the contribution of individual pathways to the development of airways hyperreactivity was partially altered by changing the route of sensitization and aeroallergen protocol (reduced with i.p. sensitization model), perhaps indicating differential activation of T cell signaling pathways under the various conditions of Ag exposure. Recently, using the noninvasive technique of whole body plethysmography (Buxco Biosytem) and direct inhalation of spasmogen to measure airways hyperreactivity (see 46 , we observed a degree of reactivity similar to that obtained in this investigation (unpublished observation).
The demonstration of an additional pathway regulating airways hyperreactivity may provide an explanation for some of the cases of asthma in which eosinophilia is not implicated with enhanced bronchial reactivity (30, 33, 41, 42). However, airways eosinophilic inflammation is a consistent and predominant finding in asthma, suggesting that the IL-5/eosinophil pathway plays a central role in the pathophysiology of the majority of cases of this disease. This evidence includes clinical and experimental investigations that show a direct correlation between eosinophils and their secretory products with the development of airways hyperreactivity and morphologic changes to the respiratory epithelium (8, 9, 10, 11, 12, 13, 43, 44, 45). Moreover, the overexpression of IL-5 or IL-4 in the respiratory epithelium led to the development of morphologic changes to the airways; however, airways hyperreactivity was restricted to the IL-5 transgenic mice (46, 47).
Two distinct physiologic pathways have been proposed as contributing to aeroallergen-induced airways hyperreactivity; one that is dependent on IL-4- and IgE-mediated activation of mast cells and another that is regulated by IL-5 and eosinophils (36). However, in the absence of IL-4 and Ag-specific IgE, aeroallergen-induced morphologic changes to the airways and enhanced reactivity to ß-methacholine were not attenuated, and a pronounced eosinophilia (albeit reduced in comparison to wild-type responses) was observed in the airways. These results with BALB/c mice, are similar to those obtained with IL-4-/- 129Sv x C57BL/6 mice (26). A significant eosinophilia and airways hyperreactivity was also observed by Corry et al. in wild-type BALB/c mice after treatment with anti-IL-4 mAbs during primary sensitization (27). Furthermore, OVA or anti-CD3 stimulation of T cells obtained from lungs of both strains of IL-4-/- mice after aeroallergen challenge also resulted in the production of significant quantities of IL-5, and in these mice Ag-induced eosinophilia and pathologic changes to the airways were abolished by treatment with anti-IL-5 mAb. However, unlike IL-4-/- 129Sv x C57BL/6 mice, aeroallergen-induced airways hyperreactivity was not abrogated by treatment with anti-IL-5 mAb in the BALB/c strain. Similarly, treating IL-5-/- BALB/c mice with anti-IL-4 mAbs during systemic sensitization did not further inhibit aeroallergen-induced airways hyperreactivity. Collectively, these investigations indicate that multiple T cell-regulated mechanisms underlie the development of airways hyperreactivity in BALB/c mice. It will be interesting to determine whether the CD4+ T cell mechanism modulating airways hyperreactivity in this strain is directly induced by novel CD4+ T cell-derived factors and/or downstream inflammatory processes.
While a number of cells and molecules contribute to the mechanism underlying the regulation of airways hyperreactivity in mice, only CD4+ T cells have been shown exclusively to regulate disease pathogenesis (48, 49, 50). Recently, the transfer of enriched naive T cell populations from a strain of mice that displayed inherent hyperreactivity to methacholine to a hyporeactive strain conferred airways hyperreactivity to this spasmogen in the absence of Ag challenge (51). The increased airways reactivity to methacholine was associated with CD4+ T cells and occurred in the absence of eosinophilia, pronounced inflammation, and morphologic changes to the airways. While the mechanism of T cell activation in the absence of Ag is obscure, these investigations support our conclusions that factors secreted from CD4+ T cells play fundamental roles in determining the level of airways reactivity to cholinergic stimuli. Moreover, there is increasing evidence that CD4+ T cell driven inflammation of the airways is a primary factor for the induction of the inflammatory cascade and bronchial hyperreactivity in asthma (1, 4, 5, 6, 10, 11, 12, 13).
In this investigation, we have shown that a pathway intimately regulated by CD4+ T cells acts independently of IL-4 and IL-5 to modulate airways hyperreactivity in BALB/c mice. IL-5-regulated eosinophilia was essential for the induction of Ag-induced morphologic changes to the airways, which also contributed to the mechanism underlying airways hyperreactivity. This investigation provides an explanation for the dissociation of eosinophilia from airways hyperreactivity in some cases of asthma and in some animal models of this disease. Furthermore, the identification of multifactorial CD4+ T cell-regulated pathways for the development of allergic airways hyperreactivity has important implications for the treatment of asthma and indicates the complex nature of the pathogenesis of allergic disease.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Paul S. Foster, Division of Biochemistry and Molecular Biology, The John Curtin School of Medical Research, Australian National University, GPO Box 334, Canberra, ACT 0200, Australia. E-mail address:
3 Abbreviations used in this paper: IL-5-/-, interleukin-5 deficient; IL-4-/-, IL-4 deficient; BALF, bronchoalveolar lavage fluid; PVDF, polyvinylidene difluoride; MBP, major basic protein.
Received for publication November 19, 1997. Accepted for publication April 6, 1998.
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K. L. Asquith, H. S. Ramshaw, P. M. Hansbro, K. W. Beagley, A. F. Lopez, and P. S. Foster The IL-3/IL-5/GM-CSF Common Receptor Plays a Pivotal Role in the Regulation of Th2 Immunity and Allergic Airway Inflammation J. Immunol., January 15, 2008; 180(2): 1199 - 1206. [Abstract] [Full Text] [PDF]
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 S. R. Barthel, M. W. Johansson, D. M. McNamee, and D. F. Mosher Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma J. Leukoc. Biol., January 1, 2008; 83(1): 1 - 12. [Abstract] [Full Text] [PDF]
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 F R. Ali, A B. Kay, and M. Larche Airway hyperresponsiveness and bronchial mucosal inflammation in T cell peptide-induced asthmatic reactions in atopic subjects Thorax, September 1, 2007; 62(9): 750 - 757. [Abstract] [Full Text] [PDF]
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J. R. Johnson, F. K. Swirski, B. U. Gajewska, R. E. Wiley, R. Fattouh, S. R. Pacitto, J. K. Wong, M. R. Stampfli, and M. Jordana Divergent immune responses to house dust mite lead to distinct structural-functional phenotypes Am J Physiol Lung Cell Mol Physiol, September 1, 2007; 293(3): L730 - L739. [Abstract] [Full Text] [PDF]
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A. Mishra, M. Wang, J. Schlotman, N. M. Nikolaidis, C. W. DeBrosse, M. L. Karow, and M. E. Rothenberg Resistin-like molecule-beta is an allergen-induced cytokine with inflammatory and remodeling activity in the murine lung Am J Physiol Lung Cell Mol Physiol, August 1, 2007; 293(2): L305 - L313. [Abstract] [Full Text] [PDF]
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D. C. Webb, Y. Cai, K. I. Matthaei, and P. S. Foster Comparative Roles of IL-4, IL-13, and IL-4R{alpha} in Dendritic Cell Maturation and CD4+ Th2 Cell Function J. Immunol., January 1, 2007; 178(1): 219 - 227. [Abstract] [Full Text] [PDF]
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 A. Hirano, A. Kanehiro, K. Ono, W. Ito, A. Yoshida, C. Okada, H. Nakashima, Y. Tanimoto, M. Kataoka, E. W. Gelfand, et al. Pirfenidone Modulates Airway Responsiveness, Inflammation, and Remodeling after Repeated Challenge Am. J. Respir. Cell Mol. Biol., September 1, 2006; 35(3): 366 - 377. [Abstract] [Full Text] [PDF]
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D. C. Kim, F. I. Hsu, N. A. Barrett, D. S. Friend, R. Grenningloh, I-C. Ho, A. Al-Garawi, J. M. Lora, B. K. Lam, K. F. Austen, et al. Cysteinyl Leukotrienes Regulate Th2 Cell-Dependent Pulmonary Inflammation J. Immunol., April 1, 2006; 176(7): 4440 - 4448. [Abstract] [Full Text] [PDF]
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 T. Koya, T. Kodama, K. Takeda, N. Miyahara, E.-S. Yang, C. Taube, A. Joetham, J.-W. Park, A. Dakhama, and E. W. Gelfand Importance of Myeloid Dendritic Cells in Persistent Airway Disease after Repeated Allergen Exposure Am. J. Respir. Crit. Care Med., January 1, 2006; 173(1): 42 - 55. [Abstract] [Full Text] [PDF]
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R. S. Peebles Jr, K. Hashimoto, J. R. Sheller, M. L. Moore, J. D. Morrow, S. Ji, J. A. Elias, K. Goleniewska, J. O'Neal, D. B. Mitchell, et al. Allergen-Induced Airway Hyperresponsiveness Mediated by Cyclooxygenase Inhibition Is Not Dependent on 5-Lipoxygenase or IL-5, but Is IL-13 Dependent J. Immunol., December 15, 2005; 175(12): 8253 - 8259. [Abstract] [Full Text] [PDF]
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 S.-W. Park, H. K. Jangm, M. H. An, J. W. Min, A.-S. Jang, J.-H. Lee, and C.-S. Park Interleukin-13 and Interleukin-5 in Induced Sputum of Eosinophilic Bronchitis: Comparison With Asthma Chest, October 1, 2005; 128(4): 1921 - 1927. [Abstract] [Full Text] [PDF]
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H. Matsuda, T. Suda, J. Sato, T. Nagata, Y. Koide, K. Chida, and H. Nakamura {alpha}-Galactosylceramide, a Ligand of Natural Killer T Cells, Inhibits Allergic Airway Inflammation Am. J. Respir. Cell Mol. Biol., July 1, 2005; 33(1): 22 - 31. [Abstract] [Full Text] [PDF]
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W. Ito, A. Kanehiro, K. Matsumoto, A. Hirano, K. Ono, H. Maruyama, M. Kataoka, T. Nakamura, E. W. Gelfand, and M. Tanimoto Hepatocyte Growth Factor Attenuates Airway Hyperresponsiveness, Inflammation, and Remodeling Am. J. Respir. Cell Mol. Biol., April 1, 2005; 32(4): 268 - 280. [Abstract] [Full Text] [PDF]
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 R. Leigh, D. S. Southam, R. Ellis, J. N. Wattie, R. Sehmi, Y. Wan, and M. D. Inman T-cell-mediated inflammation does not contribute to the maintenance of airway dysfunction in mice J Appl Physiol, December 1, 2004; 97(6): 2258 - 2265. [Abstract] [Full Text] [PDF]
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R. K. Kumar, C. Herbert, D. C. Webb, L. Li, and P. S. Foster Effects of Anticytokine Therapy in a Mouse Model of Chronic Asthma Am. J. Respir. Crit. Care Med., November 15, 2004; 170(10): 1043 - 1048. [Abstract] [Full Text] [PDF]
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 J. J. Lee, D. Dimina, M. P. Macias, S. I. Ochkur, M. P. McGarry, K. R. O'Neill, C. Protheroe, R. Pero, T. Nguyen, S. A. Cormier, et al. Defining a Link with Asthma in Mice Congenitally Deficient in Eosinophils Science, September 17, 2004; 305(5691): 1773 - 1776. [Abstract] [Full Text] [PDF]
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K. Clark, L. Simson, N. Newcombe, A. M. L. Koskinen, J. Mattes, N. A. Lee, J. J. Lee, L. A. Dent, K. I. Matthaei, and P. S. Foster Eosinophil degranulation in the allergic lung of mice primarily occurs in the airway lumen J. Leukoc. Biol., June 1, 2004; 75(6): 1001 - 1009. [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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A. E. Kelly-Welch, M. E. F. Melo, E. Smith, A. Q. Ford, C. Haudenschild, N. Noben-Trauth, and A. D. Keegan Complex Role of the IL-4 Receptor {alpha} in a Murine Model of Airway Inflammation: Expression of the IL-4 Receptor {alpha} on Nonlymphoid Cells of Bone Marrow Origin Contributes to Severity of Inflammation J. Immunol., April 1, 2004; 172(7): 4545 - 4555. [Abstract] [Full Text] [PDF]
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S. C. Dorman, R. Sehmi, G. M. Gauvreau, R. M. Watson, R. Foley, G. L. Jones, J. A. Denburg, M. D. Inman, and P. M. O'Byrne Kinetics of Bone Marrow Eosinophilopoiesis and Associated Cytokines after Allergen Inhalation Am. J. Respir. Crit. Care Med., March 1, 2004; 169(5): 565 - 572. [Abstract] [Full Text] [PDF]
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D. C. Webb, K. I. Matthaei, Y. Cai, A. N. J. McKenzie, and P. S. Foster Polymorphisms in IL-4R{alpha} Correlate with Airways Hyperreactivity, Eosinophilia, and Ym Protein Expression in Allergic IL-13-/- Mice J. Immunol., January 15, 2004; 172(2): 1092 - 1098. [Abstract] [Full Text] [PDF]
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N. M. Nikolaidis, N. Zimmermann, N. E. King, A. Mishra, S. M. Pope, F. D. Finkelman, and M. E. Rothenberg Trefoil Factor-2 Is an Allergen-Induced Gene Regulated by Th2 Cytokines and STAT6 in the Lung Am. J. Respir. Cell Mol. Biol., October 1, 2003; 29(4): 458 - 464. [Abstract] [Full Text] [PDF]
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G. S. Whitehead, J. K. L. Walker, K. G. Berman, W. M. Foster, and D. A. Schwartz Allergen-induced airway disease is mouse strain dependent Am J Physiol Lung Cell Mol Physiol, July 1, 2003; 285(1): L32 - L42. [Abstract] [Full Text] [PDF]
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T. Kobayashi, K. Iijima, and H. Kita Marked Airway Eosinophilia Prevents Development of Airway Hyper-responsiveness During an Allergic Response in IL-5 Transgenic Mice J. Immunol., June 1, 2003; 170(11): 5756 - 5763. [Abstract] [Full Text] [PDF]
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J. A. Elias, C. G. Lee, T. Zheng, Y. Shim, and Z. Zhu Interleukin-13 and Leukotrienes: An Intersection of Pathogenetic Schema Am. J. Respir. Cell Mol. Biol., April 1, 2003; 28(4): 401 - 404. [Full Text] [PDF]
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H. H. Shen, S. I. Ochkur, M. P. McGarry, J. R. Crosby, E. M. Hines, M. T. Borchers, H. Wang, T. L. Biechelle, K. R. O'Neill, T. L. Ansay, et al. A Causative Relationship Exists Between Eosinophils and the Development of Allergic Pulmonary Pathologies in the Mouse J. Immunol., March 15, 2003; 170(6): 3296 - 3305. [Abstract] [Full Text] [PDF]
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A. Kibe, H. Inoue, S. Fukuyama, K. Machida, K. Matsumoto, H. Koto, T. Ikegami, H. Aizawa, and N. Hara Differential Regulation by Glucocorticoid of Interleukin-13-induced Eosinophilia, Hyperresponsiveness, and Goblet Cell Hyperplasia in Mouse Airways Am. J. Respir. Crit. Care Med., January 1, 2003; 167(1): 50 - 56. [Abstract] [Full Text] [PDF]
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 Y. Okuda, I. Takahashi, J.-K. Kim, N. Ohta, K. Iwatani, H. Iijima, Y. Kai, H. Tamagawa, T. Hiroi, M.-N. Kweon, et al. Development of Colitis in Signal Transducers and Activators of Transcription 6-Deficient T-Cell Receptor {alpha}-Deficient Mice: A Potential Role of Signal Transducers and Activators of Transcription 6-Independent Interleukin-4 Signaling for the Generation of Th2-Biased Pathological CD4+{beta}{beta}T Cells Am. J. Pathol., January 1, 2003; 162(1): 263 - 271. [Abstract] [Full Text] [PDF]
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J. P. Justice, M. T. Borchers, J. R. Crosby, E. M. Hines, H. H. Shen, S. I. Ochkur, M. P. McGarry, N. A. Lee, and J. J. Lee Ablation of eosinophils leads to a reduction of allergen-induced pulmonary pathology Am J Physiol Lung Cell Mol Physiol, January 1, 2003; 284(1): L169 - L178. [Abstract] [Full Text] [PDF]
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R. Leigh, R. Ellis, J. Wattie, D. S. Southam, M. de Hoogh, J. Gauldie, P. M. O'Byrne, and M. D. Inman Dysfunction and Remodeling of the Mouse Airway Persist after Resolution of Acute Allergen-Induced Airway Inflammation Am. J. Respir. Cell Mol. Biol., November 1, 2002; 27(5): 526 - 535. [Abstract] [Full Text] [PDF]
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 G. W. Wong, P. S. Foster, S. Yasuda, J. C. Qi, S. Mahalingam, E. A. Mellor, G. Katsoulotos, L. Li, J. A. Boyce, S. A. Krilis, et al. Biochemical and Functional Characterization of Human Transmembrane Tryptase (TMT)/Tryptase gamma . TMT IS AN EXOCYTOSED MAST CELL PROTEASE THAT INDUCES AIRWAY HYPERRESPONSIVENESS IN VIVO VIA AN INTERLEUKIN-13/INTERLEUKIN-4 RECEPTOR alpha /SIGNAL TRANSDUCER AND ACTIVATOR OF TRANSCRIPTION (STAT) 6-DEPENDENT PATHWAY J. Biol. Chem., October 25, 2002; 277(44): 41906 - 41915. [Abstract] [Full Text] [PDF]
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S. A. Ritz, M. J. Cundall, B. U. Gajewska, D. Alvarez, J.-C. Gutierrez-Ramos, A. J. Coyle, A. N. J. McKenzie, M. R. Stampfli, and M. Jordana Granulocyte Macrophage Colony-Stimulating Factor-Driven Respiratory Mucosal Sensitization Induces Th2 Differentiation and Function Independently of Interleukin-4 Am. J. Respir. Cell Mol. Biol., October 1, 2002; 27(4): 428 - 435. [Abstract] [Full Text] [PDF]
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R. K. Kumar and P. S. Foster Modeling Allergic Asthma in Mice: Pitfalls and Opportunities Am. J. Respir. Cell Mol. Biol., September 1, 2002; 27(3): 267 - 272. [Abstract] [Full Text]
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M. Yoshida, R. Leigh, K. Matsumoto, J. Wattie, R. Ellis, P. M. O'Byrne, and M. D. Inman Effect of Interferon-{gamma} on Allergic Airway Responses in Interferon-{gamma}-deficient Mice Am. J. Respir. Crit. Care Med., August 15, 2002; 166(4): 451 - 456. [Abstract] [Full Text] [PDF]
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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. Mattes, M. Yang, S. Mahalingam, J. Kuehr, D. C. Webb, L. Simson, S. P. Hogan, A. Koskinen, A. N.J. McKenzie, L. A. Dent, et al. Intrinsic Defect in T Cell Production of Interleukin (IL)-13 in the Absence of Both IL-5 and Eotaxin Precludes the Development of Eosinophilia and Airways Hyperreactivity in Experimental Asthma J. Exp. Med., June 3, 2002; 195(11): 1433 - 1444. [Abstract] [Full Text] [PDF]
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H. FUJIMAKI, N. UI, and T. ENDO Induction of Inflammatory Response of Mice Exposed to Diesel Exhaust Is Modulated by CD4+ and CD8+ T Cells Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): 1867 - 1873. [Abstract] [Full Text] [PDF]
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D. C. Webb, A. N. J. McKenzie, and P. S. Foster Expression of the Ym2 Lectin-binding Protein Is Dependent on Interleukin (IL)-4 and IL-13 Signal Transduction. IDENTIFICATION OF A NOVEL ALLERGY-ASSOCIATED PROTEIN J. Biol. Chem., November 2, 2001; 276(45): 41969 - 41976. [Abstract] [Full Text] [PDF]
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 T. Niimi, C. L. Keck-Waggoner, N. C. Popescu, Y. Zhou, R. C. Levitt, and S. Kimura UGRP1, a Uteroglobin/Clara Cell Secretory Protein-Related Protein, Is a Novel Lung-Enriched Downstream Target Gene for the T/EBP/NKX2.1 Homeodomain Transcription Factor Mol. Endocrinol., November 1, 2001; 15(11): 2021 - 2036. [Abstract] [Full Text] [PDF]
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D. M. Walter, J. J. McIntire, G. Berry, A. N. J. McKenzie, D. D. Donaldson, R. H. DeKruyff, and D. T. Umetsu Critical Role for IL-13 in the Development of Allergen-Induced Airway Hyperreactivity J. Immunol., October 15, 2001; 167(8): 4668 - 4675. [Abstract] [Full Text] [PDF]
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M. Yang, S. P. Hogan, P. J. Henry, K. I. Matthaei, A. N. J. McKenzie, I. G. Young, M. E. Rothenberg, and P. S. Foster Interleukin-13 Mediates Airways Hyperreactivity through the IL-4 Receptor-Alpha Chain and STAT-6 Independently of IL-5 and Eotaxin Am. J. Respir. Cell Mol. Biol., October 1, 2001; 25(4): 522 - 530. [Abstract] [Full Text] [PDF]
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M. Hertz, S. Mahalingam, I. Dalum, S. Klysner, J. Mattes, A. Neisig, S. Mouritsen, P. S. Foster, and A. Gautam Active Vaccination Against IL-5 Bypasses Immunological Tolerance and Ameliorates Experimental Asthma J. Immunol., October 1, 2001; 167(7): 3792 - 3799. [Abstract] [Full Text] [PDF]
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A. Wensky, M. C. Garibaldi Marcondes, and J. J. Lafaille The Role of IFN-{gamma} in the Production of Th2 Subpopulations: Implications for Variable Th2-Mediated Pathologies in Autoimmunity J. Immunol., September 15, 2001; 167(6): 3074 - 3081. [Abstract] [Full Text] [PDF]
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M. T. Borchers, J. Crosby, P. Justice, S. Farmer, E. Hines, J. J. Lee, and N. A. Lee Intrinsic AHR in IL-5 transgenic mice is dependent on CD4+ cells and CD49d-mediated signaling Am J Physiol Lung Cell Mol Physiol, September 1, 2001; 281(3): L653 - L659. [Abstract] [Full Text] [PDF]
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 J-C Renauld New insights into the role of cytokines in asthma J. Clin. Pathol., August 1, 2001; 54(8): 577 - 589. [Abstract] [Full Text] [PDF]
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J. Mattes, M. Yang, A. Siqueira, K. Clark, J. MacKenzie, A. N. J. McKenzie, D. C. Webb, K. I. Matthaei, and P. S. Foster IL-13 Induces Airways Hyperreactivity Independently of the IL-4R{alpha} Chain in the Allergic Lung J. Immunol., August 1, 2001; 167(3): 1683 - 1692. [Abstract] [Full Text] [PDF]
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 J.C. Kips Cytokines in asthma Eur. Respir. J., July 2, 2001; 18(34_suppl): 24S - 33s. [Abstract] [Full Text] [PDF]
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P.J. Barnes Cytokine modulators as novel therapies for airway disease Eur. Respir. J., July 2, 2001; 18(34_suppl): 67S - 77s. [Abstract] [Full Text] [PDF]
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K. G. Tournoy, J. C. Kips, and R. A. Pauwels The Allergen-Induced Airway Hyperresponsiveness in a Human-Mouse Chimera Model of Asthma Is T Cell and IL-4 and IL-5 Dependent J. Immunol., June 1, 2001; 166(11): 6982 - 6991. [Abstract] [Full Text] [PDF]
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A. Tomkinson, C. Duez, G. Cieslewicz, J. C. Pratt, A. Joetham, M.-C. Shanafelt, R. Gundel, and E. W. Gelfand A Murine IL-4 Receptor Antagonist That Inhibits IL-4- and IL-13-Induced Responses Prevents Antigen-Induced Airway Eosinophilia and Airway Hyperresponsiveness J. Immunol., May 1, 2001; 166(9): 5792 - 5800. [Abstract] [Full Text] [PDF]
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J. A. Wilder, D. S. Collie, D. E. Bice, Y. Tesfaigzi, C. R. Lyons, and M. F. Lipscomb Ovalbumin aerosols induce airway hyperreactivity in naive DO11.10 T cell receptor transgenic mice without pulmonary eosinophilia or OVA-specific antibody J. Leukoc. Biol., April 1, 2001; 69(4): 538 - 547. [Abstract] [Full Text]
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 A. Nakata, O. Kaminuma, K. Ogawa, H. Fujimura, K. Fushimi, H. Kikkawa, K. Naito, K. Ikezawa, R. W. Egan, and A. Mori Correlation between eosinophilia induced by CD4+ T cells and bronchial hyper-responsiveness Int. Immunol., March 1, 2001; 13(3): 329 - 339. [Abstract] [Full Text] [PDF]
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A. TOMKINSON, G. CIESLEWICZ, C. DUEZ, K. A. LARSON, J. J. LEE, and E. W. GELFAND Temporal Association between Airway Hyperresponsiveness and Airway Eosinophilia in Ovalbumin-Sensitized Mice Am. J. Respir. Crit. Care Med., March 1, 2001; 163(3): 721 - 730. [Abstract] [Full Text] [PDF]
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T. Glaab, A. Daser, A. Braun, U. Neuhaus-Steinmetz, H. Fabel, Y. Alarie, and H. Renz Tidal midexpiratory flow as a measure of airway hyperresponsiveness in allergic mice Am J Physiol Lung Cell Mol Physiol, March 1, 2001; 280(3): L565 - L573. [Abstract] [Full Text] [PDF]
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A. Trifilieff, A. El-Hashim, and C. Bertrand Time course of inflammatory and remodeling events in a murine model of asthma: effect of steroid treatment Am J Physiol Lung Cell Mol Physiol, December 1, 2000; 279(6): L1120 - L1128. [Abstract] [Full Text] [PDF]
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K. L. Denzler, S. C. Farmer, J. R. Crosby, M. Borchers, G. Cieslewicz, K. A. Larson, S. Cormier-Regard, N. A. Lee, and J. J. Lee Eosinophil Major Basic Protein-1 Does Not Contribute to Allergen-Induced Airway Pathologies in Mouse Models of Asthma J. Immunol., November 15, 2000; 165(10): 5509 - 5517. [Abstract] [Full Text] [PDF]
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D. C. Tsitoura, S. Kim, K. Dabbagh, G. Berry, D. B. Lewis, and D. T. Umetsu Respiratory Infection with Influenza A Virus Interferes with the Induction of Tolerance to Aeroallergens J. Immunol., September 15, 2000; 165(6): 3484 - 3491. [Abstract] [Full Text] [PDF]
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K. MAGHNI, R. TAHA, W. AFIF, Q. HAMID, and J. G. MARTIN Dichotomy between Neurokinin Receptor Actions in Modulating Allergic Airway Responses in an Animal Model of Helper T Cell Type 2 Cytokine-associated Inflammation Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): 1068 - 1074. [Abstract] [Full Text]
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J. C. KIPS, K. G. TOURNOY, and R. A. PAUWELS Gene Knockout Models of Asthma Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): S66 - 70. [Full Text] [PDF]
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D. C. Webb, A. N. J. McKenzie, A. M. L. Koskinen, M. Yang, J. Mattes, and P. S. Foster Integrated Signals Between IL-13, IL-4, and IL-5 Regulate Airways Hyperreactivity J. Immunol., July 1, 2000; 165(1): 108 - 113. [Abstract] [Full Text] [PDF]
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J. G. Karras, K. McGraw, R. A. McKay, S. R. Cooper, D. Lerner, T. Lu, C. Walker, N. M. Dean, and B. P. Monia Inhibition of Antigen-Induced Eosinophilia and Late Phase Airway Hyperresponsiveness by an IL-5 Antisense Oligonucleotide in Mouse Models of Asthma J. Immunol., May 15, 2000; 164(10): 5409 - 5415. [Abstract] [Full Text] [PDF]
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D. Jankovic, M. C. Kullberg, N. Noben-Trauth, P. Caspar, W. E. Paul, and A. Sher Single Cell Analysis Reveals That IL-4 Receptor/Stat6 Signaling Is Not Required for the In Vivo or In Vitro Development of CD4+ Lymphocytes with a Th2 Cytokine Profile J. Immunol., March 15, 2000; 164(6): 3047 - 3055. [Abstract] [Full Text] [PDF]
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 A. Heinzmann, X.-Q. Mao, M. Akaiwa, R.T. Kreomer, P.-S. Gao, K. Ohshima, R. Umeshita, Y. Abe, S. Braun, T. Yamashita, et al. Genetic variants of IL-13 signalling and human asthma and atopy Hum. Mol. Genet., March 1, 2000; 9(4): 549 - 559. [Abstract] [Full Text] [PDF]
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A. W. Mould, A. J. Ramsay, K. I. Matthaei, I. G. Young, M. E. Rothenberg, and P. S. Foster The Effect of IL-5 and Eotaxin Expression in the Lung on Eosinophil Trafficking and Degranulation and the Induction of Bronchial Hyperreactivity J. Immunol., February 15, 2000; 164(4): 2142 - 2150. [Abstract] [Full Text] [PDF]
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Y. Shibata, L. A. Foster, J. F. Bradfield, and Q. N. Myrvik Oral Administration of Chitin Down-Regulates Serum IgE Levels and Lung Eosinophilia in the Allergic Mouse J. Immunol., February 1, 2000; 164(3): 1314 - 1321. [Abstract] [Full Text] [PDF]
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C. DUEZ, J. KIPS, J. PESTEL, K. TOURNOY, A.-B. TONNEL, and R. PAUWELS House Dust Mite-induced Airway Changes in hu-SCID Mice Am. J. Respir. Crit. Care Med., January 1, 2000; 161(1): 200 - 206. [Abstract] [Full Text]
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M. A. Aronica, A. L. Mora, D. B. Mitchell, P. W. Finn, J. E. Johnson, J. R. Sheller, and M. R. Boothby Preferential Role for NF-{kappa}B/Rel Signaling in the Type 1 But Not Type 2 T Cell-Dependent Immune Response In Vivo J. Immunol., November 1, 1999; 163(9): 5116 - 5124. [Abstract] [Full Text] [PDF]
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 T. R. Johnson and B. S. Graham Secreted Respiratory Syncytial Virus G Glycoprotein Induces Interleukin-5 (IL-5), IL-13, and Eosinophilia by an IL-4-Independent Mechanism J. Virol., October 1, 1999; 73(10): 8485 - 8495. [Abstract] [Full Text] [PDF]
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P. S. Foster Allergic Networks Regulating Eosinophilia Am. J. Respir. Cell Mol. Biol., October 1, 1999; 21(4): 451 - 454. [Full Text]
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M. D. Inman, R. Ellis, J. Wattie, J. A. Denburg, and P. M. O'Byrne Allergen-Induced Increase in Airway Responsiveness, Airway Eosinophilia, and Bone-Marrow Eosinophil Progenitors in Mice Am. J. Respir. Cell Mol. Biol., October 1, 1999; 21(4): 473 - 479. [Abstract] [Full Text]
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D. Jankovic, M. C. Kullberg, N. Noben-Trauth, P. Caspar, J. M. Ward, A. W. Cheever, W. E. Paul, and A. Sher Schistosome-Infected IL-4 Receptor Knockout (KO) Mice, in Contrast to IL-4 KO Mice, Fail to Develop Granulomatous Pathology While Maintaining the Same Lymphokine Expression Profile J. Immunol., July 1, 1999; 163(1): 337 - 342. [Abstract] [Full Text] [PDF]
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J. A. Wilder, D.D. S. Collie, B. S. Wilson, D. E. Bice, C. Richard Lyons, and M. F. Lipscomb Dissociation of Airway Hyperresponsiveness from Immunoglobulin E and Airway Eosinophilia in a Murine Model of Allergic Asthma Am. J. Respir. Cell Mol. Biol., June 1, 1999; 20(6): 1326 - 1334. [Abstract] [Full Text]
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 I.-C. HO, J.I. KIM, S.J. SZABO, and L.H. GLIMCHER Tissue-specific Regulation of Cytokine Gene Expression Cold Spring Harb Symp Quant Biol, January 1, 1999; 64(0): 573 - 584. [Abstract] [PDF]
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G. Grünig, M. Warnock, A. E. Wakil, R. Venkayya, F. Brombacher, D. M. Rennick, D. Sheppard, M. Mohrs, D. D. Donaldson, R. M. Locksley, et al. Requirement for IL-13 Independently of IL-4 in Experimental Asthma Science, December 18, 1998; 282(5397): 2261 - 2263. [Abstract] [Full Text]
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