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*
Department of Environmental Health Sciences, School of Hygiene and Public Health, The Johns Hopkins University, Baltimore, MD 21205; and
Wistar Institute, Philadelphia, PA 19104
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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were observed in C3H mice. Strikingly,
anti-IL-12 mAb (1 mg/mouse) treatment resulted in threefold
increases in airway reactivity in OVA-challenged resistant C3H mice,
concomitant with significant increases in bronchoalveolar lavage levels
of Th2 cytokines and decreases in IFN-. IL-12 depletion of C3H mice
also suppressed OVA-specific serum IgG2a levels and increased both
serum OVA-specific IgG1 and IgE levels. Blockade of endogenous IL-12
levels in susceptible A/J mice resulted in further augmentation of type
2 immune responses. These results demonstrate that endogenous
production of IL-12 is essential for resistance to Ag-induced airway
hyperresponsiveness, and furthermore, that dysregulation of IL-12
production may lead to the development of deleterious type 2 immune
responses to inhaled allergens. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several studies (14, 15, 16) have highlighted the predominant role of
cytokines during the initiation of antigenic stimulation in directing
the differentiation of CD4+ T cell precursors. In vitro,
using naive CD4+ T cells from TCR-
ß transgenic mice,
IL-4 and IL-12 were clearly shown to drive the development of
CD4+ T cell precursors toward, respectively, the Th2 and
the Th1 functional phenotype (15, 16). Consistent with the necessity of
IL-4 for induction of Th2 cell differentiation is the finding that
IL-4-/- mice are defective in Th2 cytokine production
(17). Conversely, IL-12 p40-/- mice are defective in
IFN- production and almost completely lack the ability to generate a
Th1 response (18). In a very well-characterized murine model of
susceptibility to leishmanial infection, skewed production of these two
critical immunoregulatory cytokines is thought to be important in
susceptibility and resistance of murine strains to infections with
Leishmania major (19). Specifically, resistance of C57BL/6J
mice to leishmanial infection is thought to be due to enhanced
production of IL-12 and/or reduced IL-4 production (20), whereas
susceptibility of BALB/c mice appears to be associated with enhanced
IL-4 production and/or reduced IL-12 production or responsiveness (21, 22). Recent in vitro studies in T cell clones derived from murine
strains exhibiting skewed cytokine patterns suggest that polarization
to a Th2 cytokine response may actually occur as a result of loss of
responsiveness of T cells to IL-12 (23). Although the exact mechanisms
of this loss of responsiveness to IL-12 are not known, these studies
highlight the importance of IL-12 signaling in prevention of harmful
type 2 responses.
In the present study, we examine the role of endogenous IL-12 in the differential susceptibility of murine strains to allergen-induced airway hyperreactivity. Our results demonstrate that IL-12 depletion induces airway hyperresponsiveness, pulmonary eosinophilia, and Th2 cytokine production following Ag exposure in formerly resistant C3H mice, while exacerbating these responses in susceptible A/J mice. These studies suggest that IL-12 plays a critical role in the regulation of airway responses to allergen provocation, and that susceptibility to the development of allergic disorders may be due to dysregulation of this critical immunoregulatory cytokine.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six-week-old male A/J and C3H/HeJ mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and were housed in a laminar flow hood in a virus-free animal facility for the duration of the experiments. The studies reported in this work conformed to the principles for laboratory animal research outlined by the Animal Welfare Act and the Department of Health, Education, and Welfare (National Institute of Health) guidelines for the experimental use of animals (n = 6–8 mice/experimental group).
Specific reagents
Anti-IL-12 mAb was prepared from hybridoma C17.8 (rat IgG2a), as previously described (24), and an isotype-matched control Ab (IgG2a) was purchased from PharMingen (San Diego, CA).
Ag challenge and anti-IL-12 mAb administration
A/J and C3H mice were sensitized by an i.p. injection of 10 µg OVA in PBS (200 µl) or PBS alone for control animals. Two weeks later, mice were challenged with 50 µl of a 1.5% solution of OVA in PBS or PBS alone for controls by aspiration, as previously described (25). To determine the effects of in vivo IL-12 depletion on the development of Ag-induced airway hyperresponsiveness, Ag-sensitized (OVA-sensitized and OVA-challenged) and control (PBS-sensitized and PBS-challenged) mice were treated by i.p. injection of either 1 mg/mouse of rat anti-mouse IL-12 (IgG1) or an isotype-matched control Ab 48 h before aspiration allergen challenge. Measurement of allergic responses was made 96 h following aspiration challenge.
Airway responsiveness measurements
Airway responsiveness to i.v. acetylcholine challenge was measured as previously described, with minor modifications (7, 13). Briefly, mice were anesthetized with sodium pentobarbital (17.5 mg/ml), intubated with a 20-gauge tracheal cannula, and ventilated at a rate of 120 breaths per minute with a constant tidal volume of air (0.2 ml). Airway pressure was measured with a pressure transducer via a port of the tracheal cannula. Muscle paralysis was provided by i.v. administration of decamethonium bromide (25 mg/kg). After establishment of a stable airway pressure recording, acetylcholine was injected i.v. (50 µg/kg) and the changes in airway pressure were recorded. Airway responsiveness was defined by the time-integrated change in peak airway pressure (airway-pressure-time index, APTI; cm H2O/s).
Assessment of airway inflammation
After airway responsiveness measurements, lungs were lavaged thoroughly with 1 ml HBSS plus 10% FBS without calcium or magnesium. The lavage fluid was centrifuged (300 x g for 10 min), and the supernatant was removed for cytokine analysis and immediately frozen at -80°C. The cells were resuspended in 1 ml HBSS plus 10% FBS and counted with a hemocytometer using trypan blue dye exclusion as a measure of viability. Cytospin slides were made and BAL cell differential percentages were determined on slide preparations stained with Diff-Quik (Baxter, McGaw, IL). At least 500 cells were differentiated by light microscopy on conventional morphologic criteria.
Quantitation of cytokine protein levels in BAL fluid
IL-4, IFN-, and IL-10 protein levels were measured in a 1-ml
volume of unconcentrated BAL fluid by sandwich ELISA, as previously
described (13). ELISAs were conducted using matching Ab pairs obtained
from PharMingen, according to the manufacturer’s instructions. The
following Ab pairs were used for ELISA detection of IL-4, IL-10, and
IFN-, respectively: BVD4-1D11 and BVD6-24G2; JES5-2A5 and SXC-1; and
R46A2 and XMG1.2. OD readings of samples were converted to picograms
per milliliter using values obtained from standard curves generated
with varying concentrations of recombinant IL-4, IL-10, and IFN-
(2000 pg/ml to 10 pg/ml). The limit of detection was 10 pg/ml for each
assay.
OVA-specific IgG1 and IgG2a ELISA assays
Sera were obtained from blood taken during exsanguination of the
animals after airway measurements. IgG subclass-specific ELISAs were
used to quantitate OVA-specific IgG1 and IgG2a Ab levels in serum.
Briefly, 96-well Corning (Corning, NY) ELISA plates were coated with 50
µl of OVA (100 µg/ml) in HBSS overnight at room temperature.
Sixteen hours later, wells were blocked by the addition of PBS/10% FBS
(200 µl/well) for 2 h at room temperature. Following blocking,
the plates were washed with PBS/Tween-20, sera were added (100
µl/well of a 1/100 dilution in PBS/1% FBS), and plates were
incubated overnight at 4°C. Plates were then washed with PBS-Tween
and incubated with biotin-conjugated anti-mouse IgG1 (1:2000;
1-chain specific) or anti-mouse IgG2a (1:2000;
2a-chain specific; PharMingen, San Diego, CA; 100
µl/well) for 1 h at room temperature. Following a final washing
procedure, plates were blotted dry and developed with 100 µl/well of
an avidin peroxidase solution (ABTS; Kirkegaard and Perry,
Gaithersburg, MD). Plates were read at 405 nm.
Quantitation of IgE
Sera were obtained from blood taken during exsanguination of the animals after airway measurements, and 100 µl (1/50 dilution in 1% FBS in PBS) was added per well. An IgE-specific ELISA was used to quantitate total IgE Ab levels in serum using matching Ab pairs (R35-72 and R32-92) obtained from PharMingen, according to the manufacturer’s instructions. OD readings (405 nM) of the samples were converted to picograms per milliliter using values obtained from standard curves generated with varying concentrations of IgE (2000 pg/ml to 5 pg/ml), and the final concentration of IgE in the serum was obtained by multiplying by the dilution factor.
Data analysis
Data are summarized as mean ± SEM. Significant treatment effects were determined using analysis of variance (Statview; Abacus Concepts, Berkeley, CA). If differences among groups were significant (p < 0.05), Fisher’s 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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To determine the effect of IL-12 depletion on the development of
allergic airway responses in resistant and susceptible strains of mice,
PBS- or OVA-challenged A/J and C3H mice were given anti-IL-12 or an
isotype-matched mAb by i.p. injection 48 h before Ag challenge. As
previously reported, airway reactivity to acetylcholine challenge in
OVA-challenged A/J mice was increased significantly compared with
PBS-challenged control mice (Fig. 1
A). In contrast, no
increase in responsiveness to acetylcholine was observed in
Ag-challenged C3H animals (Fig. 1B). Strikingly,
IL-12 blockade before Ag challenge rendered C3H mice susceptible to
Ag-induced airway hyperresponsiveness (Fig. 1B), and
exacerbated the response seen in A/J mice (Fig. 1A).
Surprisingly, IL-12 depletion of PBS-challenged mice of both strains
significantly increased their responsiveness to acetylcholine challenge
as compared with their controls (Fig. 1, A and
B). Isotype control Ab administration had no
significant effect on airway reactivity in either PBS- or
OVA-challenged mice of either strain.
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, A and B).
After Ag challenge, the number of eosinophils was increased
significantly in both A/J and C3H mice, although the total numbers of
eosinophils differed dramatically in these two mouse strains, with A/J
mice having more than 10-fold more eosinophils than C3H mice. This
Ag-induced pulmonary eosinophilia was further enhanced after depletion
of IL-12 in both strains of mice. There was no discernible effect of
anti-IL-12 treatment on eosinophil numbers in PBS-challenged mice
of either strain.
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To determine the effects of IL-12 depletion on in vivo type 1 and
type 2 cytokine production, protein levels of IL-4 and IFN- were
measured in the BAL fluids by ELISA. OVA challenge of presensitized A/J
mice significantly increased BAL levels of the type 2 cytokine, IL-4
(Fig. 3A). In contrast,
OVA challenge did not increase the levels of IL-4 in C3H mice over that
seen in control animals (Fig. 3B). Strikingly, when
OVA-exposed C3H animals were depleted of IL-12, a significant increase
in BAL levels of IL-4 levels was observed. Anti-IL-12 treatment did not
further increase IL-4 levels in OVA-challenged A/J mice, but did
increase the levels of IL-4 in A/J mice challenged with PBS. A similar
enhancement in IL-4 levels was not observed in PBS-challenged C3H
mice.
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by T cells
and NK cells (26), we determined whether depletion of endogenous IL-12
would affect IFN- production in the lungs of resistant and
susceptible mice. As we have noted previously, OVA challenge of A/J
mice did not result in significant increases in BAL levels of IFN-
when compared with their PBS controls (Fig. 4A). In contrast, OVA
challenge of resistant C3H mice resulted in a significant elevation in
IFN- levels in the BAL of C3H mice (Fig. 4B). As
expected, treatment with anti-IL-12 significantly reduced the
concentration of IFN- in OVA- and PBS-challenged mice regardless of
strain, although the results were more striking in the C3H animals.
Surprisingly, the isotype-matched control mAb increased the
concentration of IFN- in both the A/J and C3H PBS controls,
suggesting again that this control was eliciting a biologic effect.
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), whereas there was no significant
increase in C3H mice. However, depletion of IL-12 resulted in enhanced
Ag-induced IL-10 production in both A/J and C3H mice (Fig. 5),
suggesting that the endogenous production of IL-10 was down-regulated
by IL-12 in these animals. Interestingly, the isotype control mAb
decreased the Ag-induced increase in IL-10 in the A/J mice, but had no
apparent effect on the already low levels of IL-10 in the C3H
group.
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levels, these studies suggest that IL-12 may
negatively regulate the production of Th2 cytokines in vivo during
exposure to inhaled Ags. Effects of IL-12 depletion on OVA-specific IgG1 and IgG2a Ab levels
To examine the in vivo effects of IL-12 depletion on the humoral
immune response to pulmonary Ag exposure, we examined serum levels of
OVA-specific IgG1 and IgG2a Abs in PBS- and OVA-challenged mice that
received either the anti-IL-12 mAb or an isotype control Ab. This
method has been used previously to assess the relative influence of
type 1 vs type 2 cytokines in vivo, since the production of the mouse
1 subclass is augmented by IL-4 and inhibited by
IFN-, whereas that of 2a is augmented by IFN- and
inhibited by IL-4 (28, 29). As expected, the concentration of
OVA-specific Abs in the PBS control groups was not above background
(data not shown). However, the concentration of OVA-specific IgG
subclasses was increased significantly after challenge with OVA. As
shown in Figure 6, A/J mice produce
dramatically higher levels of OVA-specific IgG1 Abs than C3H mice,
while the levels of OVA-specific IgG2a Abs in the serum of the two
strains are similar. Administration of anti-IL-12 mAb before Ag
challenge significantly elevated serum levels of IgG1 in C3H mice,
while it did not result in further enhancement of serum levels of this
Ab isotype in A/J mice. Conversely, IL-12 depletion resulted in
significant suppression of serum IgG2a levels in both strains of mice.
These results support the findings from the cytokine measurements in
that C3H exhibit a type 1 cytokine response, whereas A/J exhibit a
predominant type 2 response. Following IL-12 depletion, C3H mice shift
to a type 2 response. IL-12 treatment also significantly decreased the
concentration of IgG2a found in C3H mice, confirming that
anti-IL-12 treatment significantly decreased IFN- levels in both
strains of mice. These data reinforce the concept that a switch had
occurred in C3H animals from a strong type 1 response to a type 2
response, concomitant with increased susceptibility to airway
hyperresponsiveness.
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Since IgE is thought to be important in the pathogenesis of early
and late phase allergic responses (30), we measured the total serum IgE
levels in Ag-exposed, anti-IL-12-treated and control animals. Ag
challenge significantly increased the concentration of IgE in the serum
of A/J mice over that seen in PBS-challenged controls (Fig. 7). In contrast, no Ag-induced increase
was observed in the C3H animals (Fig. 7). Administration of
anti-IL-12 before challenge significantly elevated the levels of
serum IgE in C3H mice, but did not further enhance the concentration of
IgE observed in the A/J mice. These results also support the importance
of endogenous IL-12 levels in determining the nature of the immune
response mounted in response to exposure to inhaled Ags.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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was also produced in this
strain. This conclusion is also supported by the fact that IL-12
blockade in these animals exacerbated the development of allergic
airway responses. Furthermore, the development of allergic responses in
this strain was concomitant with significant elevations in the type 2
cytokines, IL-4 and IL-10, in the lavage fluid. Conversely, in the
resistant C3H/HeJ strain, OVA-specific IgG2a levels were found with no
significant elevations in serum IgE levels or IL-4 levels. However,
significant increases in eosinophils were noted, although the magnitude
of the eosinophil response was markedly lower than in A/J mice. In
contrast to the cytokine pattern observed in A/J mice, significant
increases in IFN- levels were found in OVA-challenged C3H animals,
with no increases in IL-4 or IL-10 levels. Although IL-5 levels were
not measured in this study, due to the small quantity of BAL fluid
recoverable from individual mice, we have previously found that IL-5
levels are elevated in A/J mice, with only low levels being detected in
C3H mice. These observations suggest that both murine strains are
clearly sensitized to the Ag and develop local pulmonary responses to
the OVA challenge. Although the immune response to allergen exposure in
these strains appears to be complex, susceptibility to allergen-induced
airway hyperresponsiveness is associated with elevations in lung IL-4
production and subsequent IgE synthesis, whereas resistance is
associated with the lack of these two type 2 immune responses.
Interestingly in this model, hyperresponsiveness does not appear to
correlate with BAL eosinophilia.
As IL-12 has been shown to be the primary determinant of Th1 cell
differentiation (16, 18, 26) and has been shown to prevent development
of type 2 immune responses in several murine models of immune
activation and infection (20, 22, 31, 32), we sought to determine the
role of endogenous IL-12 production in the differential susceptibility
of A/J and C3H/HeJ mice to allergen-induced airway hyperresponsiveness.
In this study, we demonstrate that in vivo IL-12 depletion renders
normally resistant C3H mice susceptible to OVA-induced airway
hyperresponsiveness (AHR), IgE production, and type 2 cytokine
production. Specifically, IL-12 depletion resulted in significant
increases in airway responsiveness to acetylcholine in C3H mice.
Eosinophil numbers in the lavage fluid of IL-12-depleted C3H animals
were more than seven times greater compared with those observed in
OVA-sensitized C3H mice receiving the isotype-matched control Abs (Fig. 2
). In addition, a switch to a predominant IgG1 and IgE Ab profile was
observed as compared with their natural IgG2a pattern. These changes
were associated with a skewed type 2 cytokine pattern in the lungs of
OVA-challenged IL-12-depleted C3H mice compared with their
non-IL-12-depleted controls. The association of the shift to a type 2
response in the C3H animals with increases in airway
hyperresponsiveness further supports the role of type 2 responses in
the pathogenesis of airway hyperresponsiveness. Interestingly, in
susceptible A/J mice, a type 2 response is observed in the absence of
depleting IL-12 Abs and is further exacerbated following IL-12
blockade. These findings support our previous finding that
administration of IL-12 to susceptible A/J mice suppressed the
development of allergen-induced airway responsiveness concomitant with
suppression of Th2 cytokines (31), a finding that has been confirmed in
other murine models of allergic inflammation (33). The ability of IL-12
to effectively suppress type 2 cytokine production has also been shown
previously in T cells from allergic donors (34) and in
parasite-infected animals (32).
IL-12 depletion surprisingly increased airway reactivity in control animals of both strains, suggesting that endogenous cytokines influence airway tone even in the absence of overt inflammation. This increase in airway reactivity was not associated with increases in the cellularity of the BAL fluid, but was, however, associated with increases in BAL IL-4 levels in PBS-challenged A/J mice. These results suggest that the balance of IL-4 and IL-12 production in the lung may regulate processes important in maintenance of airway tone. In addition, it suggests that IL-4 even in the absence of inflammation may induce changes in airway function. However, studies in IL-4 transgenic animals, which were not hyperresponsive compared with their wild-type littermates, do not support this conclusion (35).
Many of the effects of IL-12 in vitro and in vivo are thought to be
mediated via the induction of IFN- production by T cells or NK cells
(26); however, IFN--independent effects of IL-12 have also been
reported. In this regard, we (31) have shown previously that the
inhibitory effects of IL-12 administration on Ag-induced airway
hyperresponsiveness in mice were IFN- dependent. This hypothesis is
supported by the finding that IL-12 depletion, which results in
development of hyperresponsiveness in formerly resistant C3H animals,
is associated with reduction in IFN- levels. In addition, other
studies have shown the effectiveness of both aerosol (36) and gene
delivery of IFN- (37) in inhibiting Ag-induced airway
hyperresponsiveness.
In the present study, removal of endogenous IL-12 after active immunization resulted in a switch from a predominant IgG2a Ab profile to one of IgG1 and IgE in C3H mice. This observation suggests that the lack of IgE production normally in these mice is due to the ability of endogenously produced IL-12 to suppress B cell production of IgE. These findings are consistent with both in vitro (38) and in vivo (39) studies demonstrating that IL-12 administration suppresses Ag-driven IgE production. However, several studies indicate that IL-12 is effective at suppressing IgE production only when given at the time of initial immunization (33). The reason for the effectiveness of IL-12 removal at increasing IgE levels after the initial Ag sensitization in the present study is unknown. However, a recent study by Chvatchko et al. (40) suggested that OVA challenge of mice results in production of IgE and IgG1 in the germinal center in the lung itself. Thus, IL-12 blockade at the time of lung Ag challenge in C3H mice may remove an inhibitory influence on local Ab production and allow local IgE production to occur.
The mechanism by which IL-12 suppresses Ag-driven IgE production is
unclear. As IL-12 does not directly affect B cell class switching (38),
its effect on IgE synthesis may be due to its ability to regulate the
relative quantities of IFN- and IL-4 generated by Ag-specific
lymphocytes. As these two cytokines reciprocally regulate the IgE
response, enhanced IFN- production would favor suppression of
Ag-specific IgE production as well as enhance the proportion of
IL-4-secreting T cells (41). This hypothesis is supported by the fact
that IFN- levels in C3H mice are high, whereas IL-4 levels are low
in the absence of anti-IL-12 mAb treatment. However, following
anti-IL-12 mAb adminstration, the reverse is true. However, King et
al. (38) have shown that IL-12 can suppress IgE synthesis in vitro
independently of IFN-.
The fact that IL-12 blockade in resistant C3H mice renders them susceptible to the development of allergen-induced airway hyperresponsiveness suggests that they produce high endogenous levels of IL-12 following Ag challenge of the lung. Conversely, the potentiation of allergic airway responses in A/J mice induced by IL-12 depletion would suggest that IL-12 production in the lungs of A/J mice may be reduced. Taken together with our previous finding that exogenous administration of IL-12 to A/J mice ablates their allergic responses, we may conclude that dysregulation of IL-12 production in these mice may lead to their inherent susceptibility to the development of allergen-induced airway hyperresponsiveness and type 2 cytokine pattern. Possible mechanisms for the Th2-polarized cytokine pattern in A/J mice might include alterations in genes controlling the expression of either p40 or p35 or in its receptor subunits. Conversely, alterations in genes regulating production of cytokines and/or mediators that modulate IL-12 production, such as the type 2 cytokines (i.e., IL-4, IL-13, or IL-10), TGF-ß (26), PGE2 (42), or certain complement receptors (43), may occur in A/J mice. In this regard, the enhanced production of IL-10 observed in the lavage of A/J mice may be responsible for apparently suppressed IL-12 production and subsequent polarization to a type 2 immune response. Recent studies have suggested that polarized type 2 immune response may be the result of a loss of responsiveness to IL-12 (23, 44). Studies in BALB/c mice that develop type 2 immune responses to leishmanial infection suggest that IL-4 produced early during the immune response may be responsible for the unresponsiveness of T cells to IL-12, allowing their differentiation toward a Th2 phenotype (44). As A/J mice exhibit high levels of IL-4 in response to Ag exposure, alterations in genes controlling IL-4 production may in fact be the primary defect.
The notion that dysregulated IL-12 levels may be important in allergic airway responses is supported by a recent study in human asthmatics. In this study, bronchial biopsies from asthmatic patients demonstrate fewer cells staining positive for IL-12 p40 as compared with normal controls (45). Furthermore, after successful steroid treatment, significant increases in the number of cells expressing p40 were observed. Conversely, those patients that were resistant to steroid treatment did not show an increase in the numbers of IL-12-expressing cells.
In summary, we have described a murine model of differential
susceptibility to allergen-induced airway hyperresponsiveness in which
certain murine strains are either naturally resistant or susceptible to
the development of allergic asthma. Susceptibility to airway
hyperresponsiveness and allergic inflammation is associated with a
polarized type 2 cytokine profile, whereas resistance is associated
with the production of the type 1 cytokine IFN-. We demonstrate that
natural resistance to Ag-induced airway hyperresponsiveness in murine
strains is dependent on endogenous production of IL-12, whereas
susceptibility most likely results from altered IL-12 production or
responsiveness. As our results suggest that IL-12 production and/or
signaling are critical to prevention of deleterious type 2 immune
responses in the lung following inhalation of ubiquitous allergens, the
model described herein should prove useful in elucidating the
mechanisms governing IL-12 dysregulation in allergic individuals.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Marsha Wills-Karp, School of Hygiene and Public Health, Department of Environmental Health Sciences, The Johns Hopkins University, Room 7006, 615 N. Wolfe Street, Baltimore, MD 21205.
3 Abbreviations used in this paper: BAL, bronchoalveolar lavage.
Received for publication November 11, 1997. Accepted for publication March 10, 1998.
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K. Dabbagh, M. E. Dahl, P. Stepick-Biek, and D. B. Lewis Toll-Like Receptor 4 Is Required for Optimal Development of Th2 Immune Responses: Role of Dendritic Cells J. Immunol., May 1, 2002; 168(9): 4524 - 4530. [Abstract] [Full Text] [PDF]
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J. G. Ford, D. Rennick, D. D. Donaldson, R. Venkayya, C. McArthur, E. Hansell, V. P. Kurup, M. Warnock, and G. Grunig IL-13 and IFN-{gamma}: Interactions in Lung Inflammation J. Immunol., August 1, 2001; 167(3): 1769 - 1777. [Abstract] [Full Text] [PDF]
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 J. C. Keen, L. Sholl, M. Wills-Karp, and S. N. Georas Preferential Activation of Nuclear Factor of Activated T Cells c Correlates with Mouse Strain Susceptibility to Allergic Responses and Interleukin-4 Gene Expression Am. J. Respir. Cell Mol. Biol., January 1, 2001; 24(1): 58 - 65. [Abstract] [Full Text]
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S. L. Ewart, D. Kuperman, E. Schadt, C. Tankersley, A. Grupe, D. M. Shubitowski, G. Peltz, and M. Wills-Karp Quantitative Trait Loci Controlling Allergen-Induced Airway Hyperresponsiveness in Inbred Mice Am. J. Respir. Cell Mol. Biol., October 1, 2000; 23(4): 537 - 545. [Abstract] [Full Text]
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 M. L. KAPSENBERG, C. M. U. HILKENS, T. C. M. T. van der POUW KRAAN, E. A. WIERENGA, and P. KALINSKI Atopic Allergy: A Failure of Antigen-Presenting Cells to Properly Polarize Helper T Cells? Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): S76 - 80. [Full Text] [PDF]
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J. Todt, J. Sonstein, T. Polak, G. D. Seitzman, B. Hu, and J. L. Curtis Repeated Intratracheal Challenge with Particulate Antigen Modulates Murine Lung Cytokines ,2 J. Immunol., April 15, 2000; 164(8): 4037 - 4047. [Abstract] [Full Text] [PDF]
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M. R. van Scott, J. P. Justice, J. F. Bradfield, E. Enright, A. Sigounas, and S. Sur IL-10 reduces Th2 cytokine production and eosinophilia but augments airway reactivity in allergic mice Am J Physiol Lung Cell Mol Physiol, April 1, 2000; 278(4): L667 - L674. [Abstract] [Full Text] [PDF]
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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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