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*
Johns Hopkins Asthma and Allergy Center, School of Medicine, and
Department of Environmental Health Sciences, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD 21224
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Similar features of pulmonary allergic inflammation have also been
documented in various murine models (13, 14, 15, 16, 17, 18). These studies have
provided important information regarding the role of cytokines in the
regulation of allergic inflammation. For example, it has recently been
shown that following challenge of mice with Ag, there is a significant
increase in both IL-4 and IL-5, but not IFN-
, expression in the
Ag-challenged lung, which is associated with a significant enhancement
of eosinophilia and airway hyper-responsiveness (AHR) (18, 19). Gavett
et al. (20) have recently shown that the eosinophil infiltration,
induction of airway mucus goblet cells, and AHR are dependent on the
expression of IL-4. Temann et al. (21) have also demonstrated that
mucus cells and eosinophils are present in the airways of
IL-4-transgenic mice, suggesting that excess production of mucus is
also mediated by IL-4. The importance of CD4+ T cells in
the development of Ag-induced pulmonary eosinophilia and AHR was
demonstrated by in vivo depletion of murine CD4+ T cells
(22) and by adoptive transfer of allergic responses with Ag-primed
CD4+ T cells in a rat model (23). Furthermore, Kaminuma et
al. (24) reported that transfer of IL-5-producing Th2 cell clones
induces a late phase eosinophilic infiltration in the mouse lung.
Although these studies are informative, the relative contribution of T
cells and cytokines to the induction of airway inflammatory responses
is still unclear. While it has been demonstrated that AHR can be
transferred by allergen-specific IgE and IgG1 (25), and that mast cell
activation can enhance airway responsiveness in mice (26), airway
allergic responses can occur in IgE-deficient as well as in mast
cell-deficient mice (27, 28). These latter results suggest that an
IgE-independent pathway for airway allergic responses may exist in
mice.
We hypothesized that Th2 cells are able to directly induce late allergic airway responses similar to those seen in Ag-sensitized and -challenged mice. In this study we performed pulmonary cell transfer experiments using an Ag-specific Th2 clone (D10), and the D10 cell-induced allergic responses, following activation in situ, were analyzed and compared with those of Ag-sensitized and -challenged mice.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Male AKR/J mice (6–8 wk old; The Jackson Laboratory, Bar Harbor, ME) were sensitized i.p. with 100 µg of conalbumin (CA; Sigma Chemical Co., St. Louis, MO) absorbed in 2 mg of alum in 0.4 ml of PBS on days 0 and 7. Sham-immunized mice received two injections of either PBS or alum alone. Seven days after the second sensitization, the mice were anesthetized and challenged twice (1 wk apart) intratracheally with 100 µg of CA or an irrelevant Ag, short ragweed (RW; 100 µg/mouse), in 0.05 ml of PBS. Three days after the last challenge, airway responsiveness was measured as previously described (19, 29). Airway reactivity was estimated as the time-integrated change in peak airway pressure, referred to as the airway pressure time index (centimeters of H2O per second). Following the measurement of airway responsiveness, lungs were lavaged once with 1 ml of HBSS, and the BALF cell differential counts and percentages were determined by Diff-Quik (Baxter, McGaw Park, IL) staining of cytospin slides. Five hundred cells per slide were enumerated. Aliquots of BALF were stored for the cytokine measurement. For histology, the lavaged lungs of mice from various groups were fixed in 10% buffered formaldehyde (Sigma Chemical Co.) or Hollande-Bouin’s fluid, and embedded in paraffin and glycol methacrylate. Three- to five-micron sections were stained with hematoxylin and eosin, periodic acid-Schiff’s reagent (PAS), and Alcian blue.
Cell transfer
An Ag-specific T cell clone, D10.G4.1 (D10; purchased from American Type Culture Collection, Rockville, MD), is a classic CA-specific Th2 clone derived from AKR/J mice (30). D10 cells were stimulated periodically with CA (100 µg/ml) in the presence of irradiated AKR spleen cells as APCs. Before the cell transfer, D10 cells were kept in culture for 8 days after stimulation, and the viable cells were isolated and suspended in medium containing Ag (CA, 4 mg/ml), an irrelevant Ag (RW, 4 mg/ml), or PBS. In addition, spleen cells from naive AKR mice were suspended in PBS containing Ag (CA, 4 mg/ml). Aliquots of the cell suspensions (5 x 106 cells in 0.05 ml) from various conditions were transferred intratracheally into the mouse lungs. Other control mice received Ag alone or PBS, or remained untreated. At various time points after cell transfer, airway responsiveness and BAL cell differential counts were determined as described above.
Measurement of Ag-specific IgE and BALF cytokines
Blood was obtained via the vena cava immediately following the
airway responsiveness measurement and before lavage. Levels of
CA-specific IgE were measured by ELISA. Immulon II round-bottom plates
(Dynatech Laboratories, Inc., Chantilly, VA) were coated with 25
µg/ml CA in PBS and incubated overnight at 4°C. Plates were washed
three times with PBS/0.05% Tween-20 and blocked with 1% BSA-PBS for
1 h at 37°C. After three washings, serum samples were diluted
fivefold in 1% BSA-PBS and incubated overnight at 4°C. Plates were
then washed three times, and 100 µl of goat anti-mouse IgE Ab
(0.3 µg/ml; Sigma Chemical Co.) was added to the wells for an
additional 2-h incubation at 37°C. After three washings, 100 µl of
donkey anti-goat IgG Ab conjugated with peroxidase (0.3 µg/ml)
was added for an additional 1-h incubation at 37°C. The reaction was
developed with 3,3',5,5'-tetramethylbenzidine (Bio-Rad Laboratories,
Hercules, CA) for 30 min at room temperature, stopped with 1 N
H2SO3, and read at 450 nm. The level of
IgE was calculated by comparison with a reference curve generated by
using a mouse mAb, anti-DNP IgE (Sigma Chemical Co.). Briefly,
DNP-conjugated BSA (DNP-BSA) was coated at the same concentration as
CA. After overnight incubation at 4°C, the plates were washed and
blocked as described above. Ten serial 1/2 dilutions of mouse
anti-DNP IgE starting from 1 ng/ml were added. Quantitation of
cytokine proteins, IL-4, IL-5, and IFN- was determined by ELISA
according to the manufacturer’s instructions (PharMingen, San Diego,
CA) and as described previously (29).
Monitoring of transferred Th2 cell in vivo
The polycationic molecule, 4,6-diamidino-2-phenylindole (DAPI; Sigma Chemical Co.) was used to label the D10 cells. DAPI is a fluorescent tag that strongly binds to adenosine-thymidine-rich regions of nuclear DNA through electrostatic interactions. It has been used to stain both fixed and live cells (31). An initial in vitro study demonstrated that DAPI-labeled D10 cells proliferated at the same rate as nonlabeled D10 cells (data not shown), suggesting that DAPI is nontoxic to the T cells. Briefly, D10 cells were maintained using the protocol described above. Viable cells were isolated 7 days after the last stimulation and cultured at a density of 1 x 106 in RPMI 1640 complete culture medium containing 10 µg/ml of DAPI overnight. This time period was determined by our previous kinetic study, which was optimized so that 100% of the cells were stained brightly. DAPI-stained D10 cells were then harvested, washed twice with PBS, and resuspended in PBS containing CA. Trypan blue exclusion showed that >99% of the DAPI-stained cells were viable. Cells (5 x 106) in 0.05 ml of PBS containing 200 µg of CA were transferred into naive mouse lungs by intratracheal instillation. DAPI-stained D10 cells in PBS without specific Ag were also transferred.
To evaluate the location of labeled D10 cells within the lungs and to determine whether the transferred cells migrated to extrapulmonary lymphoid tissues, lungs, spleens, brachial, axillary, and inguinal lymph nodes were fixed in 10% formalin, and 10-µm frozen sections were examined by fluorescence microscopy. Samples from naive animals were also examined. To determine the numbers of transferred D10 cells within the lung at various time points after transfer, lung cells were isolated as described by Augustin et al. (32) with slight modifications. The lungs were perfused via the right atrium with PBS, minced, and stirred in 0.5 mM EDTA in PBS at 4°C for 40 min. The cells were then pelleted and resuspended in RPMI medium. Aliquots of each cell suspension from lung isolates were placed in a hemocytometer and examined by fluorescence microscopy. Positive cells and total cell numbers were counted in at least four aliquots of each sample. Results were expressed as the average of four counts of each sample. Isolates of spleens and lymph nodes from the same animals were counted in the same manner.
Statistical analysis
Differences in inflammatory cell number and airway responsiveness among groups of mice were determined using analysis of variance (StatView, Brain Power, Inc., Calabasas, CA). When differences among groups were significant (p < 0.05), Fisher’s protected least significant difference test was used to distinguish between pairs of groups.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We first demonstrated that intratracheal challenge of sensitized
mice with Ag (CA) produces significant increases in the total numbers
of BALF cells and in the percentage of eosinophils (on the average,
73% of the BAL cells; Fig. 1
A, group CA/CA). In contrast,
in mice challenged with an irrelevant Ag (Fig. 1A, group
CA/RW), there was a significant increase in neutrophils in BALFs. These
findings demonstrate that the eosinophil infiltration is an Ag-specific
event. Airway reactivity was also determined by measuring airway
pressure changes following i.v. injection of mice with acetylcholine
(Ach). A significant increase in the airway response to Ach was
observed in mice sensitized and challenged with CA (Fig. 1B,
group CA/CA), which was associated with the increase in eosinophils in
the BALF. In contrast, when sensitized mice were challenged with RW,
there was no increase in airway responsiveness (Fig. 1B,
group CA/RW) even though a significant neutrophil influx was
observed.
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Significant levels of serum CA-specific IgE were found in all
CA-sensitized mice. No CA-specific IgE was detected in sera from
unsensitized or sham-sensitized mice at any time point. There was no
significant difference in CA-specific IgE levels between Ag- and
sham-challenged groups (Fig. 2A). The levels of both
IL-4 and IL-5, but not IFN-, expression were also significantly
increased at 24 h postchallenge in the BALFs from Ag-challenged
lungs, but declined markedly 48 h after challenge (Fig. 2B). No IL-4 or IL-5 was detected in samples
challenged with saline or RW at any time point. These results are
consistent with previous findings that the expression of Th2 cytokines
and an elevated level of serum Ag-specific IgE are associated with
airway eosinophilic inflammation and AHR in Ag-sensitized and
-challenged mice. It is not clear, however, to what extent the Th2
cells and cytokines contribute to the process of eosinophil influx and
AHR. To provide direct evidence for the role of Th2 cells in the
development of pulmonary allergic response, we performed a series of
pulmonary adoptive transfer experiments using a well-characterized
CA-specific Th2 clone (D10). The D10 cell is a classic Th2 clone
generated from AKR mice, providing an ideal cytokine delivery vehicle
following activation in situ.
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To examine the degree of pulmonary eosinophilia and
hyper-reactivity, D10 cells (5 x 106
cells/mouse) were mixed with or without CA (200 µg/mouse) or RW (200
µg/mouse) and transferred intratracheally into naive AKR mice. At 24,
48, and 72 h after cell transfer, airway reactivity to Ach was
examined, and BALF differential cell counts were performed. Results
showed that after transfer of D10+CA, only a few eosinophils (<3%)
were found in the BALF at 12 h. A significant increase in BALF
eosinophils was observed at 24 h (Fig. 3A), peaked at 48
h, and decreased slightly at 72 h. A significant increase in AHR
was observed at 48 and 72 h, and peaked at 48 h (Fig. 3B). However, pulmonary adoptive transfer of <5
x 105 D10 cells did not induce significant eosinophil
infiltration (<5%).
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A, group D10+RW; Fig. 3B, group D10+RW) showed no increase in eosinophils or AHR,
but, rather, showed a predominant neutrophil influx at 48 h, which
decreased by twofold at 72 h after cell transfer. The initial
neutrophil influx may be a nonspecific response to foreign materials,
since neutrophils were present at the early time period in BALF of
naive mice treated with Ag only or with D10 cells only, but not int
those treated with PBS. In addition, all control groups except the
D10+RW group showed no significant changes in the cell differential
counts, and all control groups showed no significant changes with time
in the level of airway responsiveness.
Local activation of the transferred D10 cells was evident by the
finding of a significant increase in both IL-4 and IL-5 (peak at
24 h), but not IFN-, secretion in the BALFs at all three time
points following pulmonary transfer of mice with D10 cells and CA (Fig. 4A). The levels of Th2
cytokines, particularly IL-5, were significantly higher in
D10-transferred mice than in Ag-sensitized and -challenged mice
(p < 0.001, for differences in the levels of
both cytokines; see also Fig. 2B, group CA/CA (24 h)). Also
of significance is the finding that no serum CA-specific IgE was
detected in mice transferred with D10 and CA compared with that in
Ag-sensitized and -challenged mice (Fig. 4B). The
decreased levels of cytokines at 72 h is probably due to the
decrease or cessation of T cell secretion or to the consumption by
other cells, such as macrophages and eosinophils, in vivo. These
results demonstrate that following Ag-specific activation of D10 cells
at the mucosal sites, there is an induction of Th2 cytokines and
eosinophil infiltration that is associated with an increase in airway
responses. However, the degrees of BALF eosinophilia and AHR were
significantly lower than those in Ag-sensitized and challenged mice
(p < 0.001 and p < 0.01,
respectively).
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To localize the transferred T cells in situ, resting D10 cells
were labeled in vitro with DAPI, a fluorescence tag (seeMaterials and Methods). DAPI-labeled D10 cells were easily
identified by fluorescence microscopy at 6, 24, 48, and 72 h
following transfer by means of their intense blue color. Endogenous
cells and nonlabeled D10 cells exhibited no blue autofluorescence.
Fluorescence microscopy demonstrated that 6 h following
intratracheal instillation, the majority of D10 cells in the lung were
localized in the vicinity of the terminal airways and appeared to be in
contact with alveolar and bronchiolar epithelium (Fig. 5A); a small number of
D10 cells appeared to have migrated into the terminal bronchioles and
alveolar walls. By 72 h, D10 cells had migrated into bronchi and
bronchioles, and some of these cells were present in the airway
epithelium (Fig. 5B). A small number of the D10 cells
was also present within the alveolar walls. Very few D10 cells were
found in either spleen or lymph node sections at any time point (one to
two cells per section) or in spleen or lymph node isolates. The latter
finding was not unexpected, since fully activated T cells recirculate
poorly (33). Quantitative analysis of DAPI-labeled D10 cells
transferred with Ag showed that the number of D10 cells in whole lung
isolates was increased 2.5-fold at 24 h, 3.5-fold at 48 h,
and 4.2-fold at 72 h compared with that at 6 h (Fig. 5C). In contrast, there was no increase in the number
of D10 cells in the absence of Ag at any time point (data not shown).
These results showed that in the presence of Ag, transferred D10 cells
were able to proliferate in the lung.
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Histologic examinations of the lungs revealed distinct differences
between different groups of mice. Lungs from sham-challenged mice
contained few, if any, inflammatory cells (Fig. 6A), and no PAS- or
alcian blue-positive mucus cells were present in the bronchial
epithelium (Fig. 6E). CA-sensitized, RW (an
irrelevant Ag)-challenged lungs, on the other hand, showed a
predominantly neutrophil infiltrate in the perivascular and
peribronchial regions (Fig. 6B), but no PAS- or
alcian blue-positive bronchial epithelial mucus cells. In contrast,
CA-sensitized, and -challenged mice exhibited perivascular and
peribronchiolar eosinophil infiltration. Numerous eosinophils were also
observed adhering to the endothelium of intrapulmonary veins.
Eosinophils were present in the smooth muscle layer of the larger
bronchi (Fig. 6C), and numerous PAS- and alcian
blue-positive mucus cells were present in the bronchial epithelium
(Fig. 6F). A similar histologic pattern was observed
in D10-cell transferred mice (Fig. 6D). Numerous
perivascular and peribronchial eosinophils were present, some of which
were located within the airway smooth muscle layer. However, while
significantly higher levels of Th2 cytokines, including IL-4, were
found in D10-transferred mice (see Fig. 5A), much
fewer mucus-containing airway epithelial cells were observed in
D10-transferred mice than in CA-sensitized and -challenged mice (Fig. 6G). In addition, no mast cells were present in
either bronchial or alveolar tissues of Ag-sensitized and -challenged
mice or D10 cell-transferred mice.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To monitor the trafficking of transferred T cells, we labeled D10 cells with DAPI before the cell transfer. As a vital stain, DAPI is relatively nontoxic and allows identification of labeled cells in vivo. In this study we demonstrated that in the presence of Ag, intratracheal transferred DAPI-labeled D10 cells not only remain in the lung for at least 72 h, but also increase in number. This finding demonstrates that the elevation of Th2 cytokines (IL-4 and IL-5) in the BALFs results from the activation of transferred D10 cells in vivo. Although the type of APCs in the lungs of these mice is presently unknown, resident macrophages and airway epithelial cells may serve as APCs when D10 cells and CA were introduced via the airways. Pulmonary transfer of T cells into the lung may thus provide a useful model to examine the detailed mechanisms of T cell- and cytokine-mediated airway inflammation and AHR. Intravenous injections of D10 cells combined with intratracheal Ag challenge did not induce either marked eosinophil infiltration or AHR (data not shown). It is likely that the transferred D10 cells do not remain in the lung long enough, or an insufficient number of cells respond to intratracheally administered Ag, since only 10% of i.v. transferred DAPI-labeled D10 cells were present in the lung at 24 h post-cell transfer.
IL-5 is an important proinflammatory cytokine controlling the
proliferation, migration, and activation of eosinophils (34, 35). IL-4
is not only critical in the regulation of IgE synthesis (36), but may
account, at least in part, for selective eosinophil recruitment to
sites of allergic reactions (37) and induction of bronchial mucus cells
(20, 21, 38). IL-4 is also important in the differentiation of Th2
cells, both in vitro and in vivo (39, 40). Studies in mice have shown
that IL-4-deficient mice do not develop eosinophilia or AHR when
sensitized and challenged with Ag (41). In addition, blockade of the
IL-4R suppressed lung eosinophilia, AHR, and increased numbers of mucus
goblet cell (20). Kaminuma et al. (23), however, reported that an
IL-5-producing T cell clone, but not an IL-4-producing T cell clone,
induces BAL eosinophils. Airway mucus cells were not examined. Studies
of cytokine gene knockout mice have found that both IL-5-dependent and
-independent inflammatory responses are associated with AHR (42, 43).
Some of these seemingly contradictory results may be due to differences
between the strain and genetic background of the mice used (44). Our
study demonstrated that although the levels of BALF IL-4 and IL-5, in
particular IL-5, are significantly higher in D10-transferred mice than
those in Ag-sensitized and -challenged mice, the levels of BALF
eosinophils, airway mucus cells, and AHR are significantly lower. These
findings suggest that there is no quantitative association between the
levels of Th2 cytokines and the degree of airway allergic responses.
Additional studies are needed to determine the relative contributions
of IL-4, IL-5, and other cytokines to the development of pulmonary
allergic responses. It is of interest to note, however, that mucosal
IFN- gene transfer inhibits both Th2 cell- and Ag-induced eosinophil
infiltration and the development of AHR (29).
The role of IgE in mast cell degranulation and mediator release in immediate allergic responses has been well established. However, the role of IgE in the late allergic inflammatory responses remains controversial (1). Several investigators have demonstrated that the development of a late asthmatic response is related to the increased level of allergen-specific serum IgE (45, 46), and that there is a significant correlation between the level of serum-specific IgE and airway responses in adults with asthma (47, 48). These observations are of particular relevance to the findings that mast cells, basophils, and tissue macrophages secrete cytokines following activation through their respective IgE receptors (1, 10, 11). However, it has been demonstrated that mucus hypersecretion is not related to serum IgE levels in adults with bronchial asthma (49). Pulmonary allergic responses in mice occur in the absence of detectable IgE (27) and mast cells (28).
Our studies of Ag- and Th2 cell-induced airway responses demonstrated
significant features similar to those observed in the Ag-challenged
lung LPR of atopic asthmatic patients (3, 4). The Th2-induced responses
in naive mice showed, however, a lesser degree and extent of allergic
responses compared with those in mice sensitized and challenged with
Ag. The comparative study of Ag- and Th2 cell-induced airway responses
demonstrated that neither the degree of eosinophil-associated AHR nor
the induction of airway mucus cells is directly correlated to the
levels of pulmonary IL-4 and IL-5. Thus, the greater responses in
sensitized and challenged mice may be attributed to IgE-mediated
activation of other cell types, such as macrophages, perhaps by
secretion of eosinophil chemotactic macrophage inflammatory
protein-1
(50). These results suggest that both IgE-dependent and
-independent activation events, either operative sequentially or in
concert, are critical to confer expression of severe allergic
responses. Thus, it is likely that activation of other cell types
together with Th2 cells may contribute to greater and sustained
allergic inflammatory responses in the airways.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Xiu-Min Li, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224-6801.
3 Abbreviations used in this paper: LPR, late phase inflammatory response; BALF, bronchoalveolar lavage fluid; AHR, airway hyper-responsiveness; CA, conalbumin; RW, ragweed; PAS, periodic acid-Schiff’s reagent; DAPI, 4,6-diamidino-2-phenylindole; Ach, acetylcholine.
Received for publication July 3, 1997. Accepted for publication October 9, 1997.
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decreases IgE production and normalizes airways function in a murine model of allergen sensitization. J. Immunol. 152:2546.[Abstract]
-gene transfer inhibits pulmonary allergic responses in mice. J. Immunol. 157:3216. (Cutting Edge). [Abstract]
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T-cell receptor. Nature 340:239.[Medline]
influences eosinophil recruitment in antigen-specific airway inflammation. Eur. J. Immunol. 25:245.[Medline]
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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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Y. Kato, T. Manabe, Y. Tanaka, and H. Mochizuki Effect of an Orally Active Th1/Th2 Balance Modulator, M50367, on IgE Production, Eosinophilia, and Airway Hyperresponsiveness in Mice J. Immunol., June 15, 1999; 162(12): 7470 - 7479. [Abstract] [Full Text] [PDF]
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J. T. Wise, T. J. Baginski, and J. L. Mobley An Adoptive Transfer Model of Allergic Lung Inflammation in Mice Is Mediated by CD4+CD62LlowCD25+ T Cells J. Immunol., May 1, 1999; 162(9): 5592 - 5600. [Abstract] [Full Text] [PDF]
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L. Li, Y. Xia, A. Nguyen, Y. H. Lai, L. Feng, T. R. Mosmann, and D. Lo Effects of Th2 Cytokines on Chemokine Expression in the Lung: IL-13 Potently Induces Eotaxin Expression by Airway Epithelial Cells J. Immunol., March 1, 1999; 162(5): 2477 - 2487. [Abstract] [Full Text] [PDF]
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X.-m. Li, C.-K. Huang, B. H. Schofield, A. W. Burks, G. A. Bannon, K.-H. Kim, S.-K. Huang, and H. A. Sampson Strain-Dependent Induction of Allergic Sensitization Caused by Peanut Allergen DNA Immunization in Mice J. Immunol., March 1, 1999; 162(5): 3045 - 3052. [Abstract] [Full Text] [PDF]
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L. Li, Y. Xia, A. Nguyen, L. Feng, and D. Lo Th2-Induced Eotaxin Expression and Eosinophilia Coexist with Th1 Responses at the Effector Stage of Lung Inflammation J. Immunol., September 15, 1998; 161(6): 3128 - 3135. [Abstract] [Full Text] [PDF]
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