The JI
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     
 

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Crosby, J. R.
Right arrow Articles by Lee, N. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Crosby, J. R.
Right arrow Articles by Lee, N. A.
The Journal of Immunology, 2002, 168: 4050-4054.
Copyright © 2002 by The American Association of Immunologists

Early Phase Bronchoconstriction in the Mouse Requires Allergen-Specific IgG1

Jeffrey R. Crosby*, Grzegorz Cieslewicz{dagger}, Michael Borchers{dagger}, Edie Hines*, Patricia Carrigan{dagger}, James J. Lee{dagger} and Nancy A. Lee2,*

Divisions of * Hematology/Oncology and {dagger} Pulmonary Medicine, Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, Scottsdale, AZ 85259


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results and Discussion
 References
 
Allergen provocation of allergic asthma patients is often characterized by an initial period of bronchoconstriction, or early phase reaction (EPR), that leads to maximal airway narrowing within 15–30 min, followed by a recovery period returning airway function to baseline within 1–2 h. In this study, we used a defined OVA provocation model and mice deficient for specific leukocyte populations to investigate the cellular/molecular origins of the EPR. OVA-sensitized/challenged wild-type (C57BL/6J) mice displayed an EPR following OVA provocation. However, this response was absent in gene knockout animals deficient of either B or T cells. Moreover, transfer of OVA-specific IgG, but not IgE, before the OVA provocation, was capable of inducing the EPR in both strains of lymphocyte-deficient mice. Interestingly, an EPR was also observed in sensitized/challenged mast cell-deficient mice following an OVA provocation. These data show that the EPR in the mouse is an immunologically based pathophysiological response that requires allergen-specific IgG but occurs independent of mast cell activities. Thus, in the mouse the initial period of bronchoconstriction following allergen exposure may involve neither mast cells nor IgE-mediated events.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results and Discussion
 References
 
Allergen provocation of asthma patients elicits a biphasic response of bronchoconstriction in ~60% of subjects, consisting of an early phase reaction (EPR)3 and a late phase reaction (LPR) (1, 2, 3, 4, 5). The EPR occurs ~15 min after allergen provocation and is thought to be mediated by resident leukocytes found in the lung such as mast cells (6). The current paradigm explaining the EPR in asthmatic subjects involves mechanisms in which allergen binds to, and cross-links, IgE receptors on mast cells (7, 8). This event subsequently leads to activation and the release of histamine and leukotrienes, triggering an immediate bronchoconstrictive response (9, 10). In contrast, the LPR begins ~3 h following allergen provocation, peaks between 6–12 h, and generally resolves within 24 h (3, 5). Hypotheses of the underlying inflammatory responses mediating the LPR are dependent on the recruitment of proinflammatory leukocytes to the lung (e.g., CD4+ T cells and eosinophils) induced directly/indirectly as a consequence of EPR-associated events, particularly the release of inflammatory mediators by resident mast cells (11, 12).

Mouse models of allergic respiratory inflammation have been particularly useful to define the immune-mediated responses occurring in the lung often with valid extrapolation to human disease. Allergen sensitization/aerosol challenge in the mouse leads to the elaboration of pulmonary cytokines characteristic of Th2 inflammatory reactions (13), a concomitant airway eosinophilia (14), and production of allergen-specific IgE and IgG1 (15). However, significant differences between mice and human subjects have also become apparent, particularly the role of allergen-specific Igs and mast cells. In contrast to human subjects, where IgE levels (i.e., atopy) are predictive of disease (16), and appear to be a critical component linking mast cell activities with pathological changes occurring in the lung (9), the role of IgE and mast cells in mouse models of allergic respiratory inflammation have been difficult to establish with several studies suggesting that no causative links exist. For example, knockout mice deficient of IgE are capable of developing pulmonary pathologies associated with allergen sensitization/challenge, including histopathologic changes of the airway epithelium and lung dysfunction (17, 18). Moreover, in the absence of IgE, mice use non-IgE-dependent pathways to elicit immediate hypersensitivity reactions such as systemic anaphylaxis (19, 20). Similarly, mast cell-deficient mice are also capable of developing pulmonary pathologies following allergen sensitization/challenge (20), although other studies suggest that mast cell contributions to pulmonary pathology are observed in other, less vigorous models of allergen challenge that typically do not include an allergen sensitization phase with adjuvant (21, 22).

The recent development of a mouse provocation model of bronchoconstriction now permits a reductionist approach to understand the mechanisms responsible for the EPR and LPR (23). In an attempt to further characterize the origins of the EPR in mice, the present study uses this provocation model as well as gene knockout animals deficient of specific leukocytes to define a mechanism(s) eliciting the EPR. Specifically, these studies demonstrate that B and T lymphocytes are each required for the EPR as a consequence of their respective roles in the production of allergen-specific Igs. The adoptive transfer of allergen-specific IgG in mice deficient of either B or T lymphocytes induced an EPR following OVA provocation. Moreover, the EPR was unique to allergen-specific IgG and did not occur following transfer of IgE, suggesting that allergen-specific IgE was incapable of eliciting this response in the mouse. Additional studies also demonstrated that the EPR occurs in mice deficient of mast cells following allergen provocation. Collectively, these data show that the EPR in the mouse, unlike asthma patients, is a pathophysiological response requiring neither IgE nor mast cell activities.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results and Discussion
 References
 
Animals

Wild-type C57BL/6J mice, gene knockout animals deficient of B cells (C57BL/6-Igh-6tm1Cgn (24)), T cells ({alpha}{beta}-/-/{gamma}{delta}-/- C57BL/6J-Tcr{beta}tm1Mom Tcr{delta}tm1Mom (25)), {alpha}{beta} TCR+ T cells (C57BL/6J-Tcr{beta}tm1Mom (25)), {gamma}{delta} TCR+ T cells (C57BL/6J-Tcr{delta}tm1Mom (26)), and mice deficient of mast cells (WBB6F1/J-KitW/KitW-v) were purchased from The Jackson Laboratory (Bar Harbor, ME). All mice were maintained in microisolator cages housed within a specific pathogen-free animal facility. The sentinel mice within this animal colony surveyed negative for known mouse pathogens. Protocols and studies involving animals were conducted in accordance with National Institutes of Health and Mayo Foundation institutional guidelines.

Experimental protocol

The allergen-provocation protocol used in this study was previously described (23). Briefly, 8–14 wk-old mice were immunized by two i.p. injections (100 µl) of OVA (20 µg; grade IV (Sigma-Aldrich, St. Louis, MO)) complexed with 2.25 mg Imject Alum (AL(OH)3/Mg(OH)2; Pierce, Rockford, IL) on days 0 and 14 of the protocol. The mice were challenged on days 24, 25, and 26 by 20-min inhalations of an aerosol generated by nebulization of a 1% OVA solution prepared in saline. Control mice received i.p. injections of saline (days 0 and 14) and 20 min aerosol challenges of saline alone (days 24, 25, and 26). All mice were provoked with an OVA aerosol (5% in saline) for 20 min 48 h after the last of the three 1% OVA (or saline) challenges (i.e., day 28) and continuous measurements of inspiratory/expiratory flow were recorded on conscious mice using whole-body plethysmography (Buxco Electronics, Troy, NY). In some studies, the highest Penh values following OVA provocation (i.e., the early phase kinetic maxima (KA)) were used to determine the increase in Penh as a percentage of baseline (BL) Penh values for each group of mice: (PenhKA - PenhBL/PenhBL) x 100.

Serum Ig levels

Serum IgE levels were determined using an immunoassay for mouse IgE (OPT EIA Mouse IgE set, catalog no. 2655k1; BD PharMingen, San Diego, CA). Anti-mouse IgE mAb (capture) was coated on flat-bottom microtiter plates (Nalge Nunc International, Naperville, IL) and incubated overnight. Standards and serum (diluted 1/2) were incubated followed by detection with biotinylated anti-mouse IgE, avidin-HRP, and tetramethylbenzidine substrate (Pierce). The limit of detection associated with this assay is ~2 ng/ml. Total IgG was determined using a mouse Ig radial immunodiffusion kit (RN272; The Binding Site, Birmingham, U.K.) as per the manufacturer’s instructions (limit of detection ~1 mg/ml). OVA-specific IgG1 serum levels were determined as previously described (27). Briefly, microtiter plates were coated overnight with 20 µg/ml chicken egg OVA. The coated plates were washed several times with PBS and blocked with 0.2% gelatin buffer (pH 8.2) for 2 h at 37°C. Serum diluted 1/10 was incubated in duplicate overnight, washed in PBS, and incubated with an alkaline phosphatase-conjugated rat anti-mouse IgG1 mAb (BD PharMingen) for 2 h. Plates were developed with a phosphatase substrate (Sigma Fast P-Nitrophenyl Phosphate (Sigma-Aldrich)) and the absorbance of each sample was measured at 410 nm using a Vmax kinetic microplate reader (Molecular Devices, Sunnyvale, CA). The detection limit of OVA-specific IgG1 using this assay system was ~0.2 OD410 U.

OVA-specific Ig isolation

Wild-type C57BL/6J mice were subjected to the OVA protocol described above. On day 28, before the 5% OVA provocation, the animals were euthanized and serum was collected from pools of {beta}10 mice, sterile filtered (0.45-µ filter; Millipore, Bedford, MA), and subjected to affinity chromatography using a 5-ml HiTrap protein G column (Amersham Biosciences, Uppsala, Sweden). The flow through from the column was collected and once again run over the column to quantitatively deplete from the serum all the IgG present. The bound IgG was washed with five-column volumes of 20 mM sodium phosphate (pH 7.0) and eluted with 0.1 M glycine-HCL (pH 2.7). The fractions eluted from the column were assayed for protein content (Bio-Rad protein assay; Bio-Rad, Hercules, CA) and pooled together. The buffer in the pooled IgG fractions and the IgG-depleted serum were each changed to PBS using Slide-Alyzers (Pierce), and equilibrated at 4°C overnight in PBS. Assessments of IgG and IgE levels in these final preparations (using the assays described above) demonstrated that IgG was absent in IgG-depleted serum and that purified mouse IgG preparations were devoid of IgE. The per mouse recovery of purified IgG was ~30 mg, whereas the amount of IgE present in IgG-depleted serum was ~300 ng/mouse.

Adoptive transfer of Igs into mice

In studies assessing the role of OVA-specific Igs, animals were injected (i.p.) with either purified IgG or IgG-depleted serum Ig from OVA-treated wild-type mice on days 22 and 24 (1 h before the 1% OVA challenge) of the provocation protocol. The amount of Ig administered was set to the amount recoverable from an OVA-sensitized/aerosol-challenged wild-type mouse (i.e., 30 mg purified IgG/mouse and IgG-depleted serum equivalent to 300 ng of IgE). Control groups of mice were administered either nonspecific mouse IgG (Sigma-Aldrich) or ragweed-specific Igs purified as described above.

Statistical analysis

Data presented are the means (±SE). Statistical analysis was performed on parametric data using Student t tests with differences between means considered significant when p < 0.05.


   Results and Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
References
 
The EPR requires both B and T lymphocytes

The involvement of B and T lymphocytes in the EPR was assessed using knockout mice deficient of either cell type. Airflow was continuously measured in groups of OVA-sensitized/challenged mice following OVA provocation and plotted as a function of the time postprovocation (Fig. 1Go). Saline sensitized/challenged C57BL/6J mice did not display an increase in Penh (i.e., airway resistance) in the first hour following allergen provocation. However, OVA-sensitized/challenged mice showed an increase within 5 min of provocation, reached maximal levels ~15 min post-OVA provocation, and returned to baseline levels within 60 min (Fig. 1GoA). This result was similar to those obtained previously with BALB/c mice (23), suggesting that the appearance of the EPR is not an inbred strain-dependent phenomena. In contrast to wild-type mice, OVA-sensitized/challenged knockout animals deficient of either B (Cµ-/-) or T ({alpha}{beta}-/-{gamma}{delta}-/-) cells were unable to develop an EPR following OVA provocation (Fig. 1GoB). In addition, further studies using knockout mice deficient of either the {alpha}{beta} TCR+ (25) or the {gamma}{delta} TCR+ (26) subpopulations of T cells showed that mice deficient of either subpopulation were not capable of eliciting an EPR (Fig. 1GoC).



View larger version (16K):
[in this window]
[in a new window]
  		FIGURE 1. B and T cells are required for the EPR following allergen provocation. Airway changes were monitored in conscious/unrestrained mice following OVA provocation using whole body plethysmography. A, OVA provocation of wild-type C57BL/6J mice sensitized/challenged with either saline (negative control) or OVA (positive control) demonstrated that the EPR occurs with a kinetic maximum 15 min following OVA provocation. B, EPR following OVA provocation do not occur in OVA-sensitized/challenged knockout mice deficient of either B or T cells. C, EPR in response to OVA provocation do not occur in OVA-sensitized/challenged knockout mice singly deficient of either the {alpha}{beta}+ or {gamma}{delta}+ T cell subpopulations. Responses to provocation are expressed as raw Penh values ± SEM (n = 10–12 mice/group). *, p < 0.05.

 
OVA-induced increases in total IgE and OVA-specific IgG1 do not occur in either B or T cell knockout mice

The lack of an EPR in B cell-deficient mice suggested that this bronchoconstrictive response was mediated by Ig, consistent with asthma patients where the EPR has been shown to result, in part, from the presence of allergen-specific IgE (28). Total serum IgE and IgG levels were measured in saline challenged control wild-type mice as well as OVA-treated wild-type, B cell, and T cell-deficient knockout mice (Fig. 2Go, A and B). These data show that although total IgE and IgG levels increase significantly in response to OVA treatment, neither Ig subtype was detectable in OVA-treated knockout mice deficient of B cells. Moreover, total serum IgE levels were undetectable in T cell-deficient mice and total IgG was reduced to a level below saline control wild-type mice. However, the presence of low levels of IgG in the serum of T cell-deficient mice, suggested that production of OVA-specific IgG in these mice was possible. In wild-type mice, OVA sensitization/challenge led to a >10-fold increase in OVA-specific IgG1, a Th2-associated (15) Ig subtype. However, OVA-specific IgG1was not detectable in T cell-deficient mice (Fig. 2GoC). The absence of an EPR and OVA-specific IgE and IgG1 in both B and T cell-deficient mice suggested that the EPR is a Th2-mediated pathophysiologic response elicited by resident pulmonary cells and/or mechanisms using one or both of these Igs. In addition, the loss or significant decrease of IgE/IgG1 production in OVA-treated knockout mice deficient of either {alpha}{beta}+ T cells (29) or {gamma}{delta}+ T cells (29, 30), respectively, suggests an explanation as to why mice singly deficient of individual T cell subpopulations do not develop an EPR following OVA provocation.



View larger version (12K):
[in this window]
[in a new window]
  		FIGURE 2. Knockout mice deficient of either B or T cells have undetectable or severely reduced levels of serum Igs. Serum Ig levels were assessed in OVA-sensitized/challenged mice just before OVA provocation (i.e., day 28). A, Total serum IgE; B, Total serum IgG; C, OVA-specific IgG1. WT Sal, saline-sensitized/challenged wild-type mice provoked with OVA; WT OVA, OVA-sensitized/challenged wild-type mice provoked with OVA; B cell (-/-), OVA-sensitized/challenged B cell-deficient (i.e., Cµ-/-) mice provoked with OVA; T cell (-/-); OVA-sensitized/challenged T cell-deficient (i.e., {alpha}{beta}-/-{gamma}{delta}-/-) mice provoked with OVA. Data represent mean values ± SEM (n = 5–6 mice/group). *, p < 0.05.

 
Early phase bronchoconstriction in the mouse is mediated exclusively by allergen-specific IgG and occurs independently of mast cells

The EPR in humans has been extensively studied and is likely a consequence of allergen-mediated cross-linking of IgE-Fc{epsilon}R on mast cells initiating events leading to degranulation and the release of inflammatory mediators (e.g., histamine and leukotrienes) precipitating bronchoconstriction (7, 9). In contrast to this working model in humans, reconstitution of OVA-sensitized/challenged B cell-deficient mice with IgG-depleted serum from OVA-sensitized/challenged wild-type animals, restoring serum total IgE to wild-type levels in the recipients (i.e., 122 ± 5 ng/ml), did not elicit an EPR following OVA provocation (Fig. 3GoA). However, the restoration of wild-type levels of serum IgG in B cell-deficient mice by the transfer of IgG from OVA-sensitized/challenged wild-type mice (i.e., 13.2 ± 1.6 mg/ml) was sufficient to mediate an EPR following OVA provocation that was comparable to the responses observed in wild-type animals (Fig. 3GoA). The Ag specificity of this response was demonstrated by the inability of serum IgG or IgG-depleted serum (i.e., IgE) from ragweed-sensitized/aerosol-challenged mice to induce an EPR following OVA provocation or OVA-sensitized/aerosol-challenged mice (Fig. 3GoB). The recovery of the EPR also did not require prior exposure to allergen; transfer of OVA-specific IgG into naive B cell-deficient mice also induced an EPR following OVA provocation (Fig. 3GoC). These data thus limit T cell participation in the EPR to helper functions necessary for allergen-specific Ig production by B cells. This conclusion was confirmed by Ig transfer experiments using T cell-deficient ({alpha}{beta}-/-{gamma}{delta}-/-) mice (Fig. 4Go). Transfer of IgG from OVA-sensitized/challenged wild-type mice into OVA-sensitized/challenged T cell-deficient animals was again sufficient to induce an EPR following OVA provocation equivalent to the responses observed in wild-type animals.



View larger version (20K):
[in this window]
[in a new window]
  		FIGURE 3. The EPR following OVA provocation is induced in OVA-sensitized/challenged or naive B cell-deficient mice following transfer of IgG, but not IgE, from OVA-sensitized/challenged wild-type mice. A, The kinetic maxima of the EPR from OVA-provoked saline and OVA-treated wild-type mice (WT) are shown in comparison to the maximal bronchoconstriction displayed by B cell-deficient mice concurrently administered (i.p.) either saline (no IgG), serum IgG-derived from OVA-sensitized/challenged wild-type mice (OVA-serum IgG), nonspecific mouse IgG (control IgG), or IgG-depleted serum Igs from OVA-sensitized/challenged wild-type mice (OVA-IgG-depleted serum). B, Transfer of serum IgG or IgG-depleted serum from ragweed-sensitized/aerosol-challenged mice does not induce an early phase response following OVA provocation of OVA-sensitized/aerosol-challenged B cell-deficient (B cell (-/-)) animals. Wild-type mice were sensitized/aerosol challenged with ragweed using the protocol of Sur et al. (35 ) before the isolation of serum Igs as described in Materials and Methods. C, Transfer of serum IgG from OVA-sensitized/challenged wild-type mice (OVA-serum IgG) elicits an early phase response in naive B cell-deficient mice. Data represent mean values ± SEM (n = 7–10 mice/group). Baseline Penh values of each group of mice are as follows: A, WT saline = 0.42 ± 0.06; WT OVA = 0.41 ± 0.01; (B cell (-/-) OVA) No IgG = 0.45 ± 0.06; (B cell (-/-) OVA) OVA-serum IgG = 0.44 ± 0.09; (B cell (-/-) OVA) Control IgG = 0.46 ± 0.07; (B cell (-/-) OVA) OVA-IgG-depleted serum = 0.39 ± 0.04. B, (B cell (-/-) OVA) OVA-serum IgG = 0.30 ± 0.01; (B cell (-/-) OVA) ragweed-serum IgG = 0.32 ± 0.04; (B cell (-/-) OVA) No IgG = 0.30 ± 0.02; (B cell (-/-) OVA) ragweed-IgG-depleted serum = 0.37 ± 0.03. C, (B cell (-/-) naive) Control IgG = 0.34 ± 0.02 and (B cell (-/-) naive) OVA-serum IgG = 0.30 ± 0.01.

 


View larger version (16K):
[in this window]
[in a new window]
  		FIGURE 4. The EPR following OVA provocation is induced in OVA-sensitized/challenged T cell-deficient ({alpha}{beta}-/-/{gamma}{delta}-/-) mice following transfer of IgG from OVA-sensitized/challenged wild-type mice. The kinetic maxima of the EPR from OVA-provoked saline and OVA-treated wild-type mice (WT) are shown in comparison to the maximal bronchoconstriction displayed by T cell-deficient mice concurrently administered (i.p.) either saline (No IgG), serum IgG-derived from OVA sensitized/challenged wild-type mice (OVA-serum IgG), or nonspecific mouse IgG (control IgG). Data represent mean values ± SEM (n = 7–10 mice/group). Baseline Penh values of each group of mice are as follows: WT saline = 0.37 ± 0.05; WT OVA = 0.31 ± 0.02; (T cell (-/-) OVA) No IgG = 0.35 ± 0.02; (T cell (-/-) OVA) OVA-serum IgG = 0.30 ± 0.02; (T cell (-/-) OVA) Control IgG = 0.34 ± 0.04.

 
The observation that the EPR occurred in the presence of allergen-specific IgG, and was not induced following transfer of allergen-specific IgE, requires that any mechanism to explain the EPR in the mouse must rely exclusively on allergen-specific IgG. The implicit assumption is that this IgG-dependent mechanism will be analogous to IgE pathways in humans and is still mast cell-mediated, requiring allergen-specific IgG and the Fc{gamma}R known to be on mast cells (for example, see Ref. 31). However, this extrapolation is not supported by the observation that OVA provocation of sensitized/challenged mast cell-deficient mice resulted in an EPR (Fig. 5Go). Thus, in this model system mast cells are not necessary for the EPR. Unfortunately, the definitive character of this result is complicated by the controversial role of mast cells in the lungs of mice. These leukocytes are not a prevalent resident cell population of the lungs of mice (32, 33) and OVA sensitization/challenge of mast cell-deficient mice, similar to wild-type animals, leads to a host of pulmonary pathologies, including goblet cell metaplasia/mucus production and the development of airway hyperresponsiveness (34). However, two recent studies (21, 22) have suggested that the contributory role of mast cells to inflammatory responses in the lungs of mice is dependent on the "asthma model" studied. These studies propose that mast cells are "amplifiers" of allergen-mediated pathology whose importance is demonstrable using relatively "weak" protocols typically lacking a sensitization phase using an adjuvant. Thus, while no role for mast cells in the EPR is observed in the sensitization/challenge model used in this study, the issue of mast cell contributions to early phase bronchoconstriction using other protocols remains possible.



View larger version (17K):
[in this window]
[in a new window]
  		FIGURE 5. The EPR occurs in sensitized/challenged mast cell-deficient mice following OVA provocation. The kinetic maxima of the EPR from OVA-provoked saline and OVA-treated mast cell-sufficient control mice (Kit w-v/+/+) are shown in comparison to the maximal bronchoconstriction displayed by mast cell-deficient mice (Kitw/Kitw-v). Data represent mean values ± SEM (n = 6–12 mice/group). Baseline Penh values of each group of mice are as follows: (Kit w-v/+/+) Saline = 0.47 ± 0.07; (Kit w-v/+/+) OVA = 0.40 ± 0.04; (Kitw/Kitw-v) Saline = 0.45 ± 0.06; (Kitw/Kitw-v) OVA = 0.40 ± 0.04.

 
The demonstration that the EPR in this sensitization/challenge mouse model requires neither IgE nor mast cell activities provides a compelling argument that an as yet unknown pulmonary leukocyte, using exclusively allergen-specific IgG, may be responsible for this pathophysiologic response. However, the mechanism-eliciting effector function is likely, in principle, to be similar to IgE-mediated mast cell degranulation in the human lung, inducing an EPR in the mouse as a consequence of mediators released following allergen-induced cross-linking of IgG-Fc{gamma}R on this leukocyte.


   Acknowledgments
 
We thank Drs. Erwin Gelfand and Michael Lahn for ongoing discussions and advice as the study progressed. A critical review of the manuscript by Dr. Michael McGarry was invaluable to the clarity of the work presented. Special thanks go to the Mayo Clinic Scottsdale Graphic Arts Facility (Director, Marv Ruona) as well as our research program assistant Linda Mardel and her colleague Bonnie Broadhead; without this administrative staff we could not function as an integrated group or a productive laboratory.


   Footnotes
 
1 This work was supported by National Heart, Lung, and Blood Institute Individual Investigator Award HL-60793-01S (to N.A.L.) and National Research Service Award HL-10176 (to J.R.C.). Back

2 Address correspondence and reprint requests to Dr. Nancy A. Lee, Division of Hematology/Oncology, Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, 13400 East Shea Boulevard, Scottsdale, AZ 85259. E-mail address: nlee{at}mayo.edu Back

3 Abbreviations used in this paper: EPR, early phase reaction; LPR, late phase reaction. Back

Received for publication November 19, 2001. Accepted for publication February 11, 2002.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results and Discussion
 References
 

  1. Booij-Noord, H., K. de Vries, H. J. Sluiter, N. G. Orie. 1972. Late bronchial obstructive reaction to experimental inhalation of house dust extract. Clin. Allergy 2:43.[Medline]
  2. Robertson, D. G., A. T. Kerigan, F. E. Hargreave, R. Chalmers, J. Dolovich. 1974. Late asthmatic responses induced by ragweed pollen allergen. J. Allergy Clin. Immunol. 54:244.[Medline]
  3. Cockcroft, D. W., R. E. Ruffin, J. Dolovich, F. E. Hargreave. 1977. Allergen increases nonallergic bronchial reactivity. Clin. Allergy 7:505.
  4. Warner, J. O.. 1976. Significance of late reactions after bronchial challenge with house dust mite. Arch. Dis. Child. 51:905.[Abstract/Free Full Text]
  5. Durham, S. R.. 1991. The significance of late responses in asthma. Clin. Exp. Allergy 21:3.
  6. Picado, C.. 1992. Early and late-phase asthmatic reactions: a hypothesis. Allergy 47:331.[Medline]
  7. Wasserman, S. I.. 1988. Basic mechanisms in asthma. Ann. Allergy 60:477.[Medline]
  8. Boulet, L. P., K. R. Chapman, J. Cote, S. Kalra, R. Bhagat, V. A. Swystun, M. Laviolette, L. D. Cleland, F. Deschesnes, J. Q. Su, et al 1997. Inhibitory effects of an anti-IgE Ab E25 on allergen-induced early asthmatic response. Am. J. Respir. Crit. Care Med. 155:1835.[Abstract]
  9. Flint, K. C., K. B. Leung, B. N. Hudspith, F. L. Pearce, J. Brostoff, N. M. Johnson. 1986. The function and properties of human lung mast cells. Respiration 50:31.
  10. Durham, S. R., C. F. Craddock, W. O. Cookson, M. K. Benson. 1988. Increases in airway responsiveness to histamine precede allergen-induced late asthmatic responses. J. Allergy Clin. Immunol. 82:764.[Medline]
  11. deMonchy, J., I. J. Kauffman, P. Venge. 1985. Bronchoalveolar eosinophilia during allergen-induced late-phase asthmatic reactions. Am. Rev. Respir. Dis. 131:373.[Medline]
  12. Metzger, W. J., D. Zavala, H. B. Richerson, P. Moseley, P. Iwamota, M. Monick, K. Sjoerdsma, G. W. Hunninghake. 1987. Local allergen challenge and bronchoalveolar lavage of allergic asthmatic lungs: description of the model and local airway inflammation. Am. Rev. Respir. Dis. 135:433.[Medline]
  13. Ohkawara, Y., X. F. Lei, M. R. Stampfli, J. S. Marshall, Z. Xing, M. Jordana. 1997. Cytokine and eosinophil responses In the lung, peripheral blood, and bone marrow compartments in a murine model of allergen-induced airways inflammation. Am. J. Respir. Cell Mol. Biol. 16:510.[Abstract]
  14. Tomaki, M., L. L. Zhao, J. Lundahl, M. Sjostrand, M. Jordana, A. Linden, P. O’Byrne, J. Lotvall. 2000. Eosinophilopoiesis in a murine model of allergic airway eosinophilia: involvement of bone marrow IL-5 and IL-5 receptor {alpha}. J. Immunol. 165:4040.[Abstract/Free Full Text]
  15. Finkelman, F. D., J. Holmes, I. M. Katona, Jr J. F. Urban, M. P. Beckmann, L. S. Park, K. A. Schooley, R. L. Coffman, T. R. Mosmann, W. E. Paul. 1990. Lymphokine control of in vivo immunoglobulin isotype selection. Annu. Rev. Immunol. 8:303.[Medline]
  16. Peat, J. K., B. G. Toelle, J. Dermand, R. van den Berg, W. J. Britton, A. J. Woolcock. 1996. Serum IgE levels, atopy, and asthma in young adults: results from a longitudinal cohort study. Allergy 51:804.[Medline]
  17. Korsgren, M., J. S. Erjefält, O. Korsgren, F. Sundler, C. G. A. Persson. 1997. Allergic eosinophil-rich inflammation develops in lungs and airways Of B cell-deficient mice. J. Exp. Med. 185:885.[Abstract/Free Full Text]
  18. Hamelmann, E., K. Takeda, J. Schwarze, A. T. Vella, C. G. Irvin, E. W. Gelfand. 1999. Development of eosinophilic airway inflammation and airway hyperresponsiveness requires interleukin-5 but not immunoglobulin E or B lymphocytes. Am. J. Respir. Cell Mol. Biol. 21:480.[Abstract/Free Full Text]
  19. Oettgen, H. C., T. R. Martin, A. Wynshaw-Boris, C. Deng, J. M. Drazen, P. Leder. 1994. Active anaphylaxis in IgE-deficient mice. Nature 370:367.[Medline]
  20. Miyajima, I., D. Dombrowicz, T. R. Martin, J. V. Ravetch, J. P. Kinet, S. J. Galli. 1997. Systemic anaphylaxis in the mouse can be mediated largely through IgG1 and Fc{gamma}RIII: assessment of the cardiopulmonary changes, mast cell degranulation, and death associated with active or IgE- or IgG1-dependent passive anaphylaxis. J. Clin. Invest. 99:901.[Medline]
  21. Kobayashi, T., T. Miura, T. Haba, M. Sato, I. Serizawa, H. Nagai, K. Ishizaka. 2000. An essential role of mast cells in the development of airway hyperresponsiveness in a murine asthma model. J. Immunol. 164:3855.[Abstract/Free Full Text]
  22. Williams, C. M., S. J. Galli. 2000. Mast cells can amplify airway reactivity and features of chronic inflammation in an asthma model in mice. J. Exp. Med. 192:455.[Abstract/Free Full Text]
  23. Cieslewicz, G., A. Tomkinson, A. Adler, C. Duez, J. Schwarze, K. Takeda, K. A. Larson, J. J. Lee, C. G. Irvin, E. W. Gelfand. 1999. The late, but not early, asthmatic response is dependent on IL-5 and correlates with eosinophil infiltration. J. Clin. Invest. 104:301.[Medline]
  24. Kitamura, D., J. Roes, R. Kuhn, K. Rajewsky. 1991. A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin µ chain gene. Nature 350:423.[Medline]
  25. Mombaerts, P., A. R. Clarke, M. A. Rudnicki, J. Iacomini, S. Itohara, J. J. Lafaille, L. Wang, Y. Ichikawa, R. Jaenisch, M. L. Hooper, et al 1992. Mutations in T-cell antigen receptor genes {alpha} and {beta} block thymocyte development at different stages [Published erratum appears in 1992 Nature 360:491]. Nature 360:225.[Medline]
  26. Itohara, S., P. Mombaerts, J. Lafaille, J. Iacomini, A. Nelson, A. R. Clarke, M. L. Hooper, A. Farr, S. Tonegawa. 1993. T cell receptor {delta} gene mutant mice: independent generation of {alpha}{beta} T cells and programmed rearrangements of {gamma}{delta} TCR genes. Cell 72:337.[Medline]
  27. Saloga, J., H. Renz, G. Lack, K. L. Bradley, J. L. Greenstein, G. Larsen, E. W. Gelfand. 1993. Development and transfer of immediate cutaneous hypersensitivity in mice exposed to aerosolized antigen. J. Clin. Invest. 91:133.
  28. Kay, A.. 1989. Inflammatory cells in bronchial asthma. J. Asthma 26:331.[Medline]
  29. Schramm, C. M., L. Puddington, C. A. Yiamouyiannis, E. G. Lingenheld, H. E. Whiteley, W. W. Wolyniec, T. C. Noonan, R. S. Thrall. 2000. Proinflammatory roles of T-cell receptor (TCR) {gamma}{delta} and TCR {alpha}{beta} lymphocytes in a murine model of asthma. Am. J. Respir. Cell Mol. Biol. 22:218.[Abstract/Free Full Text]
  30. Zuany-Amorim, C., C. Ruffie, S. Haile, B. B. Vargaftig, P. Pereira, M. Pretolani. 1998. Requirement for {gamma}{delta} T cells in allergic airway inflammation. Science 280:1265.[Abstract/Free Full Text]
  31. Sylvestre, D. L., J. V. Ravetch. 1996. A dominant role for mast cell Fc receptors in the Arthus reaction. Immunity 5:387.[Medline]
  32. Temann, U. A., G. P. Geba, J. A. Rankin, R. A. Flavell. 1998. Expression of interleukin 9 in the lungs of transgenic mice causes airway inflammation, mast cell hyperplasia, and bronchial hyperresponsiveness. J. Exp. Med. 188:1307.[Abstract/Free Full Text]
  33. Van Overveld, F. J., L. A. Houben, F. E. Schmitz du Moulin, P. L. Bruijnzeel, J. A. Raaijmakers, G. K. Terpstra. 1989. Mast cell heterogeneity in human lung tissue. Clin. Sci. 77:297.[Medline]
  34. Takeda, K., E. Hamelmann, A. Joetham, L. D. Shultz, G. L. Larsen, C. G. Irvin, E. W. Gelfand. 1997. Development of eosinophilic airway inflammation and airway hyperresponsiveness in mast cell-deficient mice. J. Exp. Med. 186:449.[Abstract/Free Full Text]
  35. Sur, S., J. Lam, P. Bouchard, A. Sigounas, D. Holbert, W. J. Metzger. 1996. Immunomodulatory effects of IL-12 on allergic lung inflammation depend on timing of doses. J. Immunol. 157:4173.[Abstract]



This article has been cited by other articles:


Home page
 Eur Respir JHome page
A. R. Ressmeyer, A. K. Larsson, E. Vollmer, S. E. Dahlen, S. Uhlig, and C. Martin
Characterisation of guinea pig precision-cut lung slices: comparison with human tissues
Eur. Respir. J., September 1, 2006; 28(3): 603 - 611.
[Abstract] [Full Text] [PDF]

Home page
 J. Immunol.Home page
C. Taube, C. Duez, Z.-H. Cui, K. Takeda, Y.-H. Rha, J.-W. Park, A. Balhorn, D. D. Donaldson, A. Dakhama, and E. W. Gelfand
The Role of IL-13 in Established Allergic Airway Disease
J. Immunol., December 1, 2002; 169(11): 6482 - 6489.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Respir. Crit. Care Med.Home page
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]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Crosby, J. R.
Right arrow Articles by Lee, N. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Crosby, J. R.
Right arrow Articles by Lee, N. A.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS