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-Chain on APCs in the Development of Allergen-Induced Airway Hyperresponsiveness and Inflammation1
* Department of Medicine II, Faculty of Medicine, Okayama University Medical School, Okayama, Japan;
Department of Pediatrics, Division of Cell Biology, National Jewish Medical and Research Center, Denver, CO; and
Department of Experimental Immunology and Core Research for Evolutional Science and Technology Program, Japan Science and Technology Agency, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
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Abstract |
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-chain (FcR) is an essential component of the receptors Fc
RI, FcRI, and FcRIII, which are expressed on many inflammatory cell types. The role of these receptors in the initiation or maintenance of allergic inflammation has not been well defined. FcR-deficient (FcR–/–) and control (wild-type (WT)) mice were sensitized and subsequently challenged with OVA. Following sensitization and challenge to OVA, FcR-deficient (FcR–/–) mice developed comparable levels of IgE and IgG1 as WT mice. However, numbers of eosinophils, levels of IL-5, IL-13, and eotaxin in bronchoalveolar lavage fluid, and mononuclear cell (MNC) proliferative responses to OVA were significantly reduced, as was airway hyperresponsiveness (AHR) to inhaled methacholine. Reconstitution of FcR–/– mice with whole spleen MNC from WT mice before sensitization restored development of AHR and the numbers of eosinophils in bronchoalveolar lavage fluid; reconstitution after sensitization but before OVA challenge only partially restored these responses. These responses were also restored when FcR–/– mice received T cell-depleted MNC, T and B cell-depleted MNC, or bone marrow-derived dendritic cells before sensitization from FcR+/+ or FcRIII-deficient but not FcR–/– mice. The expression levels of FcRIV on bone marrow-derived dendritic cells from FcR+/+ mice were found to be low. These results demonstrate that expression of FcR, most likely FcRI, on APCs is important during the sensitization phase for the development of allergic airway inflammation and AHR. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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-chain (FcR) is a key component of several of these receptors. The high-affinity IgE receptor (FcRI), the high-affinity IgG receptor (FcRI), and the low-affinity IgG receptors (FcRII, FcRIII, and recently identified FcRIV) all contain an ITAM that is essential for immune cell activation through cytosolic protein kinases (1, 2, 3). Many of these cell types also express a unique inhibitory FcR for IgG, FcRIIb, which contains an ITIM in its cytoplasmic domain. Engagement of the activating FcRs triggers many biological functions including phagocytosis, degranulation, cytolysis, and the transcriptional activation of genes encoding many of the cytokines involved in allergic lung inflammatory responses. In addition, FcRs mediate the uptake of immune complexes, their degradation, and, ultimately, peptide Ag presentation on macrophages and DC (4, 5).
In bronchial asthma, the role of allergen-specific Abs is important, and serum levels of allergen-specific IgE and disease severity have been closely correlated. As a corollary, anti-IgE therapy in severe atopic asthmatics has been demonstrated to be effective (6). However, in a number of studies in mice, a role for allergen-specific Abs has not been demonstrated nor required for the development of AHR and allergic airway inflammation (7, 8, 9, 10). In addition to the high-affinity receptor for IgE, expression of FcRII (CD23), the low-affinity IgE receptor may also be involved in the development of airway eosinophilia (11). Indirectly, the efficacy of i.v. Ig treatment in severe asthma (12) may indicate that inhibitory FcR-mediated activation of cells by IgG or immune complexes can be a potent regulator of allergic airway inflammation and that targeting the FcR pathway could control airway allergic responses.
To determine the role of activating-type FcRs in the development of allergen-induced AHR and airway inflammation, we investigated the responses of FcR-deficient (FcR–/–) mice following allergen sensitization and challenge. FcR–/– mice failed to develop AHR or allergic airway inflammation, and this deficiency was localized to abnormalities of APC function.
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Materials and Methods |
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FcR-deficient (FcR–/–) mice from 6 to 8 wk of age were used. These mice were derived as described previously (13). As controls, FcR-sufficient C57BL/6 (wild-type (WT)) mice and FcRIII-deficient (FcRIII–/–) mice were purchased from The Jackson Laboratory or Charles River Laboratories. Mice with a disruption of the JH gene (B cell–/–, C57BL/6 background) (14) were provided by Dr. L. Wysocki (National Jewish Medical and Research Center, Denver, CO). All mice were maintained on an OVA-free diet under specific pathogen-free conditions. Experiments were conducted under a protocol approved by the Institutional Animal Care and Use Committee of Okayama University Medical School and the National Jewish Medical and Research Center.
Sensitization and airway challenge
Mice received the following treatments: PBS/OVA, challenged alone to aerosolized OVA; OVA/OVA, sensitized to OVA (together with alum) followed by aerosolized airway challenge with nebulized OVA. Sensitization was achieved by immunization i.p. with 20 µg of OVA (grade V; Sigma-Aldrich) emulsified in 2.25 mg of alum (Imject Alum; Pierce) in a total volume of 100 µl on days 1 and 14. Mice were challenged via the airways with OVA (1% in saline) for 20 min on days 28, 29, and 30 by ultrasonic nebulization (NE-U07; OMRON) and assessed 48 h after the last OVA exposure.
Measurement of serum levels of anti-OVA Ab
Peripheral blood samples were collected by cutting the inferior vena cava after measurements of airway responsiveness, and serum was separated. Serum levels of OVA-specific-IgE and IgG1 were determined by ELISA (15). The Ab titers of the samples were related to pooled standards containing OVA-specific IgE and IgG1 generated from OVA-sensitized and -challenged BALB/c mice and expressed as ELISA units per milliliter.
Bronchoalveolar lavage (BAL) and measurement of cytokine levels
BAL fluid was collected with 1 ml of saline via the tracheal tube 48 h after the last airway challenge. For differential cell counts, slides were prepared with a Cytospin III (Thermo Shandon) and cells were stained with May-Giemsa. BAL fluid cytokine levels for IL-5, IL-4, IL-13, and eotaxin levels were determined by ELISA (R&D Systems).
Spleen and peribronchial lymph node (PBLN) mononuclear cell (MNC) proliferation
MNC from spleen and PBLN were purified by density gradient centrifugation (Histopaque-1083; Sigma-Aldrich). Cells were counted and resuspended in culture medium (IMDM; Invitrogen Life Technologies) containing heat-inactivated FCS (Sigma-Aldrich), 2-ME (Sigma-Aldrich), 100 U/ml penicillin (Banyu Pharmaceutical), and 100 µg/ml streptomycin (Meiji Seika Kaisha). Cells were plated at 1 x 106/ml in 96-well round-bottom tissue culture plates in triplicate and incubated with medium alone or containing OVA (1, 10, and 100 µg/ml) for 72 h. Cell proliferation was assessed by uptake of [3H]thymidine, which was added to cell culture wells for the last 6 h of the incubation period. After incubation, cells were harvested onto a glass-fiber filter paper using a cell harvester apparatus and the incorporated radiolabel was counted using a gamma spectrometer (TRI-CARB 2260XA; Packard Japan).
Histological studies
Forty-eight hours after the last airway challenge, lungs were inflated with 1 ml of 10% formalin through the trachea, and fixed in formalin by immersion. Tissue blocks of lung tissue from four to five mice in each group were cut from around the main bronchus and embedded in paraffin blocks; two to three tissue sections (5 µm) per mouse were then affixed to microscope slides and deparaffinized. The slides were then stained with H&E or periodic acid-Schiff (PAS). Cells containing eosinophilic major basic protein (MBP) were identified by immunohistochemical staining as previously described using rabbit anti-mouse MBP (provided by Dr. J. J. Lee, Mayo Clinic, Scottsdale, AZ) (15). Photographs of the slides were taken with a microscope (BX40; Olympus) equipped with a digital camera (Q-color 3; Olympus) and images were stored on a Macintosh computer. The numbers of eosinophils were counted and adjusted by area. Goblet cell metaplasia was quantified as the number of pixels on the computer converted from PAS+ areas along the airway epithelium. The quantification was performed using NIH Scion Image software (version 1.63), available on the Internet at 
http://rsb.info.nih.gov/nih-image
. Six to eight different fields per slide were examined in a blinded manner.
Determination of airway responsiveness
Airway responsiveness was assessed as changes in airway function after challenge with aerosolized methacholine (MCh; Sigma-Aldrich). Mice were anesthetized, tracheostomized, mechanically ventilated, and lung function was assessed as described previously (16). Ventilation was achieved at 160 breaths per minute at a tidal volume of 0.16 ml with a positive end-expiratory pressure of 2–4 cm H2O with a ventilator (SN-480-7; Shinano Seisakusho). Lung resistance (RL) was continuously computed (Labview; National Instruments) by fitting flow, volume, and pressure to an equation of motion using a recessive least-squares algorithm.
Aerosolized MCh was administered through bypass tubing via an ultrasonic nebulizer (model 5500D; DeVilbiss) placed between the expiratory port of the ventilator and the four-way connector. Aerosolized MCh was administered for 8 s with a tidal volume of 0.45 ml and frequency of 60 breaths per minute using another ventilator (model 683; Harvard Apparatus). The data of RL were continuously collected for up to 3 min and maximum values were taken.
Adoptive transfer of spleen cells
Spleen MNC were purified by gradient centrifugation, resuspended in PBS, and transferred to recipient mice through the tail vein (1 x 107 cells in 200 µl). Five hours after cell transfer, mice were sensitized to OVA or challenged with OVA in previously sensitized mice. In some MNC preparations, T cells were depleted (T cell-depleted) from either WT or B cell-deficient (T and B cell-depleted) mice by treatment with anti-Thy1.2 Ab (H.0.13) and rabbit complement (Low-Tox-M; Cedarlane Laboratories). Following treatment, the number of CD3+ cells was <5% in both WT and B cell–/– mice, respectively; B220+ cells were 88 and 3% in WT and B cell–/–, respectively; NK cells were 3 and 50%, respectively; and CD11c+ were 4 and 20%, respectively.
Adoptive transfer of bone marrow-derived DC (BM-DC)
Bone marrow-derived DC (BM-DC) from WT, FcR–/–, or FcRIII–/– mice were generated as described previously (17), with some modifications. Briefly, bone marrow cells obtained from femurs and tibias of mice were placed in culture flasks at 37°C in DC culture medium (RPMI 1640 containing 10% heat-inactivated FCS, 50 µM 2-ME, 2 mM L-glutamine, 100 U/ml penicillin, and 100 µg/ml streptomycin (Invitrogen Life Technologies), 10 ng/ml recombinant mouse GM-CSF, and 10 ng/ml recombinant mouse IL-4 (R&D Systems)). After 2 h of culture, nonadherent cells were collected and continued in culture. On day 5, nonadherent cells were collected again and resuspended in fresh DC culture medium. On day 7, the nonadherent cells were collected and 0.5 x 106 were injected i.p. into recipient mice before sensitization. More than 90% of the transferred cells expressed CD11c. To determine the expression levels of FcRIV on BM-DC, cells were stained with anti-FcRIV mAb (9E9-Alexa Fluor 647, provided by Drs. J. Ravetch and F. Nimmerjahn, The Rockefeller University, New York, NY) and analyzed by flow cytometry (FACSCalibur; BD Biosciences).
Statistical analysis
All results were expressed as the mean ± SEM as a standard method of presentation for this type of data. The t test was used to determine differences between two groups and the Tukey-Kramer test was used for comparisons between multiple groups. Measured values may not be normally distributed and due to the small sample sizes this is difficult to test for. Nonparametric analysis using the Mann-Whitney U test was also used to confirm that the statistical differences remained significant even if the underlying distribution was uncertain. The p values for significance were set to 0.05 for all tests.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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-deficient mice
As shown in Fig. 1, following sensitization and challenge with OVA, WT mice developed increases in lung resistance to inhaled MCh in a dose-dependent manner and a marked increase in BAL total cell numbers, comprised in large part by increased numbers of eosinophils when compared with challenged-only mice. FcR–/– mice failed to show such increases in lung resistance following sensitization and challenge and demonstrated significantly lower numbers of eosinophils in the BAL fluid (and total cell counts) when compared to WT mice.
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In parallel to the findings in BAL fluid, H&E-stained lung tissue sections showed increased numbers of inflammatory cells, including eosinophils, in the peribronchial regions in sensitized and challenged WT mice compared with challenged-only WT mice (Fig. 2, A and C). In contrast, sensitization and challenge to OVA did not induce a similar accumulation of inflammatory cells in the lung tissue of FcR–/– mice (Fig. 2, B and D). PAS-stained lung sections also revealed that FcR–/– mice failed to develop the degree of airway goblet cell metaplasia observed in WT mice after allergen sensitization and challenge (Fig. 2, E and F).
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As shown in Fig. 3, serum levels of anti-OVA IgE and IgG1 in FcR–/– mice were comparable to WT mice after sensitization and challenge with OVA. These Abs were not detectable in the challenged-only WT or FcR–/– mice (data not shown). The Ab data confirmed the ability of these deficient mice to respond to sensitization and challenge, at least in some of the responses.
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After sensitization and challenge to OVA, IL-4, IL-5, IL-13, and eotaxin levels in the BAL fluid were measured (Fig. 4). In the sensitized and challenged WT mice, levels of all four proteins increased compared with challenged-only mice. IL-4 levels in BAL fluid were barely detectable and no significant differences were observed in the levels of IL-4 in BAL fluid of sensitized and challenged FcRI–/– and WT mice. The levels of IL-5, IL-13, and eotaxin in sensitized and challenged FcR–/– mice were significantly lower. Levels of IFN- were similar in WT and deficient mice (data not shown).
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As measured by tritiated thymidine incorporation, proliferative responses to OVA in MNC from the PBLN and spleen were significantly lower in FcR–/– mice compared to WT mice following sensitization and challenge (Fig. 5). PBLN cells from challenged-only mice were not available because the lymph nodes were small and cell yields very low.
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–/– mice with spleen MNC
MNC were prepared from spleens of naive mice and adoptively transferred into FcR+/+ or FcR–/– mice before sensitization and challenge. Transfer of spleen MNC from FcR+/+ mice followed by sensitization and challenge to OVA restored both airway responsiveness and allergic airway inflammation in FcR–/– mice (Fig. 6, A and B). When FcR–/– mice received spleen MNC after sensitization but before OVA challenge, the extent of reconstitution of airway responsiveness, inflammation, and the number of eosinophils in BAL was significant (compared with mice challenged alone), but limited when compared with the results following their transfer before sensitization (Fig. 6, C and D). Transfer of spleen MNC from FcR–/– mice into either WT or deficient mice failed to alter the responses (data not shown).
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+/+ MNC and FcR-deficient BM-DCs
To determine which donor cell types expressing FcR may have contributed to the reconstitution effects of spleen MNC on development of AHR and allergic airway inflammation, FcR–/– recipient mice were studied following transfer of T cell-depleted or T and B cell-depleted spleen MNC from FcR+/+ mice before sensitization (Fig. 7, A–C). Both T cell and T/B cell-depleted FcR+/+ MNC restored AHR; the number of eosinophils; and the levels of IL-4, IL-5, IL-13, and eotaxin in BAL fluid to the same levels as following adoptive transfer of whole-spleen MNC into WT recipients. IL-4 levels were increased but in each group were low. There were no significant differences in any of the cytokine/chemokine levels between WT recipients and FcR–/– recipients.
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–/– mice may be tied to defective APC function. To address this directly, BM-DC were differentiated from FcR+/+, FcR–/–, or FcRIII–/– mice and transferred into FcR–/– mice. FcR–/– recipients fully developed increases in RL (Fig. 8A), lung eosinophilia (Fig. 8, B and C), and goblet cell metaplasia (Fig. 8, D and E) when they received BM-DC from FcR+/+ and FcRIII–/– but not FcR–/– mice. The expression levels of FcRIV on BM-DC by flow cytometric analysis revealed very low levels of FcRIV on BM-DC from WT mice compared with BM-DC from FcR–/– (Fig. 8F).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionDisclosuresReferences |
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–/– mice were shown to develop significantly lower AHR to inhaled MCh as well as decreased BAL and lung tissue inflammation, eosinophilia, and goblet cell metaplasia. These decreased responses were accompanied by lower levels in the BAL fluid of IL-5, IL-13, and eotaxin, as well as decreased Ag-specific T cell proliferative responses. The results of these studies indicate that deletion of FcR results in the failure to develop allergen-induced AHR, eosinophilic inflammation, Th2 cytokine responses, and goblet cell metaplasia, all features of the response in mice normally expressing FcR. Somewhat surprising, and unexplained at present, were the findings that allergen-specific Ab responses remained intact. Thus, despite the absence of FcR expression on B cells, the deficient mice were nonetheless able to respond to allergen sensitization and challenge with specific Ab production. In other systems as well, specific Ab production has been demonstrated in mice that lack FcR (18), or where APC function was inhibited (19).
The involvement of FcRs and those associated with FcR in particular have not been extensively examined in models of allergen-induced AHR and airway inflammation. Deletion of the FcR-chain results in the deficiency of activating-type FcRs, including FcRI, FcRIII, and FcRI, but does not affect the expression or inhibitory function of FcRIIb. Deletion of FcR also results in the deficiency of other receptors such as paired Ig-like receptor A, but the phenotype of paired Ig-like receptor A deficiency resulting from deletion of FcR is not clear (20). To some extent, it appears that the consequence of a specific deficiency of an activating-type FcR in mice depends on the approach taken to elicit AHR and airway inflammation. For example, following allergen challenge of sensitized mice, neutrophils are the first inflammatory cells found in BAL fluid. In FcR–/– mice, the number of neutrophils and levels of neutrophil chemokines in BAL fluid were significantly reduced compared with FcR+/+ animals; absence of FcRI was without effect on these responses (21). Furthermore, investigation of this neutrophil response showed that it was Ab-dependent and mediated through FcRIII (21). Interestingly, development of AHR and eosinophilic inflammation following sensitization and challenge was independent of this neutrophil response, indicating that the failure to express FcRIII in the FcR–/– mice could not account for the absence of AHR, inflammation, and goblet cell metaplasia (22).
Following 10 days of airway exposure to allergen in the absence of systemic sensitization or adjuvant, or following passive sensitization with allergen-specific IgE (or IgG1) followed by limited airway challenge, the development of AHR and airway inflammation was dependent on the expression of FcRI (23). This is contrasted by the approach used in the present study where sensitization to allergen was systemic, together with alum as an adjuvant, followed by allergen challenge. In this case, there are no requirements for B cells or Abs, including allergen-specific IgE, FcRI, or mast cells (9, 16). Nonetheless, in FcR–/– mice, sensitization and challenge failed to elicit AHR, lung eosinophilia, or goblet cell metaplasia. The absence of eosinophilia in the BAL fluid or lung tissue was likely associated with the significantly lower levels of IL-5 and eotaxin (24), whereas the marked decreased in goblet cell metaplasia was likely the consequence of the failure to produce adequate amounts of IL-13 (25).
Genetic deletion of FcR has resulted in the attenuation or decreased susceptibility to various autoimmune diseases such as collagen-induced arthritis (26), vasculitis (27), glomerulonephritis (28), or Alzheimer’s disease (29). Deficiency of the FcR also has been shown to impair the development of NK cell-mediated Ab-dependent cytotoxicity (13) and to impair the development of anaphylaxis (30, 31, 32); in the absence of FcRIIb, anaphylaxis was enhanced (33). One of the critical functions of FcRs is their ability to enhance Ag presentation by the APCs in the lung the DC (2, 34). Most FcRs efficiently internalize Ag-Ab complexes and induce the processing of Ags into peptides that are presented by MHC class I and class II molecules in vitro (2). In humans, FcRIIa and FcRIIb were shown to regulate DC function toward either activation or inhibition, respectively (35). This implies that FcRs have a pivotal role in augmenting humoral and cellular immune responses at the level of Ag presentation and at the initiation of the response.
Based on the role FcRs play in DC function, we showed that provision of spleen MNC, including T-depleted and T/B cell-depleted MNC, fully restored all of the allergen-induced responses in the lung, including altered airway function, inflammation, goblet cell metaplasia, and Th2 cytokine and chemokine levels. Because DC alone reconstituted the responses, the data were suggestive of defective DC function in the FcR–/– mice. This was confirmed in experiments generating BM-DC from FcR+/+ or FcR–/– mice. To further address the role of the FcR chain in DC activity, DC reconstitution experiments were conducted in FcR–/– mice. DC from either FcR+/+ or FcRIII–/– mice fully reconstituted all of the responses. As well, because DC from FcR+/+ mice were found to express very low levels of FcRIV, it was unlikely that FcRIV contributed to the responses. Although, Nimmerjahn et al. (3) showed FcRIV expression on BM-DC, because DC were cultured with IL-4 in this study it is possible that Th2-type cytokines may have down-regulated FcRIV expression (3). Taken together, all of the data related to FcR function, including the findings that deficiency of FcRI resulted in impaired Ag presentation (36, 37), the absence of expression of FcRI on mouse DCs, the low expression of FcRIV, and the reconstitution experiments point to the essential role of FcRI in DC function for the full development of lung allergic responses.
There are two distinguishable phases for development of these lung allergic responses, the initial sensitization phase and the second airway challenge phase. APC function is almost certainly required at both stages of the response. Lung DC function likely predominates in the airway allergen challenge phase, whereas a number of APCs may be activated during the sensitization phase, especially when adjuvant is given together with allergen. For maximum reconstitution of all of the lung allergic responses, MNC or DC had to be transferred to recipients during the period of sensitization; when given after sensitization was completed, but before airway challenge, the responses in FcR–/– recipients were lower, but nonetheless were present. It is not entirely clear why this is the case other than to suggest that at least some of the priming that does occur during the sensitization phase, especially when alum is coadministered, has systemic effects including effects in the lung, even in the absence of FcR. These findings support the necessity of FcR at both phases for full development of the responses, but because transfer before challenge was effective, at least some of the sensitization could be achieved in the absence of FcR. This is supported by the findings of normal Ag-specific Ab levels in the serum which develop almost entirely during the sensitization phase. Conceivably, the incorporation of alum in the sensitization phase bypasses some of the requirements for FcR in this phase, and the normal Ab development may be related to the ability of alum alone to trigger IL-4 production (38).
Regnault et al. (5) showed that BM-DC derived from FcR–/– mice failed to mature normally or promote efficient MHC class I-restricted presentation of peptides from exogenous IgG-complexed Ags Interestingly, presentation of soluble Ag (at higher concentrations than IgG-complexed Ags) was also impaired in FcR-deficient DC. FcR-dependent Ag uptake by DC in the absence of specific IgG Ab may also represent a form of cross-priming, which is evident in DC (5). In addition, FcR ligation by non-Ig molecules such as C-reactive protein (39) or amyloid P (40), which increase during inflammatory responses and can opsonize particles, may also activate critical FcR-expressing cells. We previously described that B cell-deficient mice, which fail to make specific Ab of any isotype, fully develop AHR and airway inflammation following systemic allergen sensitization and airway challenge (9). It is not entirely clear what role FcR plays in the absence of engagement of FcR by IgG. However, following systemic sensitization and challenge or priming of DC with allergen before adoptive transfer and allergen challenge, FcR has been shown to be essential to AHR development as suggested by inhibition of the FcR-related signaling molecule Syk (19). Furthermore, in some T cell subsets such as double-negative T regulatory cells, FcR forming a complex with CD3 may play a functional role in these cells through activation of Syk (41). This may indicate a distinctive role for FcR, independent of IgG ligation, as observed in B cell-deficient mice.
In summary, expression of FcR is important in the development of allergen-induced AHR and inflammation. Beyond the role of FcRI mediating mast cell activation, the importance of FcR expression was clearly demonstrated in a model independent of a need for IgE-FcRI-mast cells. FcR expression was linked in this approach to APC function with full reconstitution of all responses when APCs expressing FcR were injected into FcR–/– recipients before sensitization; even when administered after sensitization and before challenge, APCs expressing FcR were capable of reconstituting lung allergic responses, albeit to a lower level than when injected during sensitization. These findings identify the potential of targeting activating FcRs in the treatment of asthma.
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Acknowledgments |
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Disclosures |
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Footnotes |
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1 This work was supported by National Institutes of Health Grants HL-36577 and HL-61005 and Environmental Protection Agency Grant R825702. 
2 K.K. and K.T. contributed equally to this study.
3 The laboratories of E.W.G. and M.H. contributed equally to this study.
4 Address correspondence and reprint requests to Dr. Erwin W. Gelfand, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail address: gelfande{at}njc.org
5 Abbreviations used in this paper: DC, dendritic cell; AHR, airway hyperresponsiveness; WT, wild type; BAL, bronchoalveolar lavage; PBLN, peribronchial lymph node; MNC, mononuclear cell; PAS, periodic acid-Schiff; MBP, major basic protein; MCh, methacholine; RL, lung resistance; BM-DC, bone marrow-derived DC.
Received for publication December 9, 2005. Accepted for publication October 4, 2006.
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References |
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  C. von Garnier, M. E. Wikstrom, G. Zosky, D. J. Turner, P. D. Sly, M. Smith, J. A. Thomas, S. R. Judd, D. H. Strickland, P. G. Holt, et al. Allergic Airways Disease Develops after an Increase in Allergen Capture and Processing in the Airway Mucosa J. Immunol., November 1, 2007; 179(9): 5748 - 5759. [Abstract] [Full Text] [PDF]
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