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,
Center for Immunology and Departments of
*
Internal Medicine and
Pathology and
Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110
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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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CD4+ Th cells can be divided into phenotypic subsets based
on the cytokines they produce (reviewed in 9 . Th1 cells secrete
IFN-
, IL-2, and lymphotoxin and promote immunity to intracellular
pathogens such as Listeria as well as Ig class switching to
IgG2a. Th2 cells secrete IL-4, IL-5, IL-6, IL-10, and IL-13 and promote
immune responses to helminthic infections as well as Ig class switching
to IgG1 and IgE. Once an immune response begins to deviate toward a Th1
or a Th2 response, there is potential for further polarization of the
Th response mediated by the cytokines produced by the Th cells
themselves. IFN- from Th1 cells promotes IL-12R expression on T
cells and activates macrophages to produce IL-12 that promotes
differentiation of naive T cells into Th1 cells 10 . IFN- also
inhibits proliferation of Th2 cells. IL-4 and IL-10 promote
differentiation of naive T cells into Th2 cells and also down-regulate
macrophage function and Th1 activation 11 . Thus, each subset has the
potential to promote its own expansion while inhibiting the
differentiation of the other.
Because of the associations of asthma with IgE and eosinophil
predominant inflammation, it has been suggested that a relative
imbalance of Th2 responses over Th1 responses drives the pathogenesis
of the disease. It has been further suggested that Th1 responses in the
lung may protect against asthma 2, 3, 4, 5, 6, 12 . In support of this model,
BAL T cells from human asthmatics have been reported to express
elevated levels of IL-4 and IL-5 mRNA 8, 13 . In addition, an inverse
association between Th1 tuberculin responses and asthma has been
observed 12, 14 . In mouse models of asthma, CD4+ cells,
IL-4, and IL-5 are all essential for the development of eosinophilic
lung inflammation 15, 16, 17, 18, 19 . Other studies have demonstrated that the
Th1-associated cytokines, IL-12 and IFN-, can inhibit allergic
inflammation 20, 21, 22 . However, additional experiments have shown
increased numbers of IFN--producing T cells in BAL fluid from human
asthmatics 23, 24 . Also, viral infections of the respiratory tract,
which can induce Th1 responses, are one of the most commonly recognized
triggers of asthmatic exacerbations (reviewed in 25 .
To better elucidate the respective roles of Th1 and Th2 cells in allergic lung inflammation, we have applied intracellular cytokine staining and flow cytometry to study T cells in a mouse model of Ag-induced asthma. In addition, we have tested the ability of passively transferred Ag-specific Th1 and Th2 cells to modulate allergic lung inflammation. Here we show that both Th1 and Th2 cells are recruited to the lung in sensitized mice after challenge. Skewing toward a Th1 response by passive transfer of Th1 cells increases lung inflammation, regardless of whether the cells are transferred before sensitization or after airway inflammation is established. Transfer of Th2 cells has little effect. Transferring Th1 cells promotes the recruitment of endogenous Th1 cells, but also increases the number of infiltrating endogenous Th2 cells and other inflammatory cells. These data indicate that Th1 cells are inefficient at inhibiting inflammation in this model. Rather, they may augment the inflammatory response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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BALB/c mice were obtained from Harlan Sprague-Dawley (Indianapolis, IN). DO11.10 TCR transgenic mice 26 were backcrossed >10 times to the BALB/c background before the initiation of these experiments. The transgenic TCR was maintained in a heterozygous fashion by backcrossing to BALB/c. All mice used in these experiments were females, 4–6 wk of age at the time of initial immunization. Mice were housed in a specific pathogen-free facility with food and water provided ad libitum.
Induction of airway hypersensitivity
Mice were sensitized to OVA (Sigma-Aldrich, St. Louis, MO) and challenged according to a modification of the method of Kung et al. 27 . Groups of three to six mice were immunized i.p. with 8 µg OVA adsorbed to 2 mg alum (Sigma-Aldrich) in 0.5 ml PBS. The mice received an identical booster immunization 7 days later. On day 15 and day 21 after the initial sensitization, mice were challenged with an aerosol of 1% (w/v) OVA in PBS in a plexiglass chamber for 20 min both in the morning and afternoon of each challenge day. The aerosol was generated by a DeVilbiss Ultra-Neb 99 nebulizer (De Vilbiss, Somerset, PA). Vehicle control mice received mock sensitization with i.p. injections of alum in PBS and were challenged with an aerosol of PBS without OVA.
Analysis of airway and lung inflammation
When indicated, airway inflammatory cells were obtained by BAL. Mice were anesthetized by i.p. injection of ketamine/xylazine and sacrificed by cervical dislocation. The trachea was cannulated and the lungs were flushed with four 0.8 ml aliquots of ice cold 2% FCS in PBS. RBCs in the lavage were lysed using ammonium chloride, and nucleated cells were counted by a hemacytometer. Lavage samples from three mice were pooled for analysis of intracellular cytokines. Lung parenchymal T cells were prepared from minced tissue that had been digested for 30 min at 37°C with collagenase/dispase (1 mg/ml; Boehringer Mannheim, Indianapolis, IN) and DNase I (0.1 mg/ml, Boehringer Mannheim) in complete medium. The tissue was then homogenized between ground glass slides and strained through a 70-µm nylon mesh to generate a single cell suspension. CD4+ cells were purified from the suspension using anti-mouse CD4 Dynabeads and mouse CD4 DETACHaBEAD (Dynal, Lake Success, NY) according to the manufacturer’s instructions. Cells from three mice were pooled for analysis of intracellular cytokines.
Analysis of intracellular cytokines
Total BAL or purified parenchymal CD4+ T cells were
cultured at 37°C in Iscove’s medium supplemented with 10% FCS
(HyClone, Logan, UT), 0.01 mM nonessential amino acid mix, 2 mM sodium
glutamate, 1 mM sodium pyruvate, 100 U/ml penicillin, 100 µg/ml
streptomycin, and 5.5 µM 2-ME (all from Life Technologies, Grand
Island, NY) (T cell medium) for 6 h in the presence of 2 µM
monensin (Sigma-Aldrich) with or without 10 ng/ml PMA (Sigma-Aldrich)
and 1 µM ionomycin (Sigma-Aldrich). CD4+ cells were
marked using allophycocyanin-anti-CD4 (PharMingen, San Diego, CA).
Cells were fixed for 30 min in 4% paraformaldehyde in PBS,
permeabilized with 0.1% saponin, and then stained with
phycoerythrin (PE) anti-IFN- (PharMingen) and either
FITC-anti-IL-4 (PharMingen) or FITC-anti-IL-5 (PharMingen).
Anti-CD4 and anti-IFN- were used at 1:100 dilution;
anti-IL-4 and anti-IL-5 were used at 1:50. Transgenic DO11.10 T
cells were stained with biotinylated anti-clonotypic Ab KJ1–26
26 followed by streptavidin-CyChrome (PharMingen). Samples were
analyzed using a FACSCalibur Becton Dickinson flow cytometer (Mountain
View, CA). The forward scatter and side scatter properties of the cells
were used to exclude dead cells from analysis. For BAL cells,
one-fourth of the cells collected were analyzed; for purified
CD4+ parenchymal cells, 10,000 cells were analyzed.
Preparation of differentiated CD4+ T cells
OVA-specific Th1 and Th2 cells were generated in vitro as
described previously 28 . Briefly, FACS-sorted CD4+
L-selectin+ T cells from lymph nodes and spleens of DO11.10
TCR transgenic mice were cultured with irradiated splenocytes at a
ratio of 1:20 for 3 days in the presence of 0.3 µM
OVA323–339 peptide. For Th1 cultures, IL-12 (2 ng/ml; R&D
Systems, Minneapolis, MN) and anti-IL-4 (10 µg/ml, 11B11) were
added. For Th2 cultures, IL-4 (1000 U/ml; R&D Systems) and
anti-IL-12 (TOSH; 10 µg/ml, courtesy of Dr. E. Unanue,
Washington University) 31 were added. On day 3, cells were expanded
1:4 and IL-2 (40 U/ml; R&D Systems) was added. On day 7, cells were
frozen in FCS containing 10% DMSO. Before transfer into recipient
mice, cells were thawed and restimulated with irradiated APCs and 0.3
µM OVA peptide. Supernatants for ELISA were collected at 48 h.
After 72 h, the cells were expanded 1:4 in medium with 40 U/ml
IL-2. IFN- and IL-4 concentrations in the supernatants were measured
using Quantikine ELISA kits (R&D Systems) according to the
manufacturer’s instructions. Supernatants from the Th1 cells contained
<0.04 ng IL-4/ml and 1200 ng IFN-/ml. Th2 supernatants contained
4.2 ng IL-4/ml and only 2.5 ng IFN-/ml. The cells were also analyzed
by flow cytometry. Th1 cells expressed IFN- but little IL-4 or IL-5,
whereas Th2 cells expressed IL-4 and IL-5 but little IFN- (see Fig. 4
). In addition, surface expression of membrane lymphotoxin was
demonstrated on Th1, but not Th2, cells by staining with biotinylated
soluble lymphotoxin ß receptor fusion protein (kindly provided by J.
Browning, Biogen, Cambridge, MA).
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Cells differentiated as above were harvested 8 or 9 days after restimulation with the OVA peptide in the presence of APCs, washed in sterile PBS, and transferred to recipient mice by i.v. injection in 0.5 ml of PBS. For transfers to unsensitized mice, groups of four animals received 25 x 106 or 5 x 106 Th1 cells, mock transfers, or 25 x 106 or 5 x 106 Th2 cells the day before being sensitized with i.p. injections as described above. The mice were challenged 7 days after the booster injection and sacrificed 3 days later. For transfers after challenge, groups of five mice received 25 x 106 Th1, mock transfers, or 25 x 106 Th2 cells the day after the first challenge. The following day the mice were rechallenged, and 3 days later they were sacrificed.
Histology
For staining with hematoxylin and eosin (H&E), lungs were inflated and fixed with 10% buffered formalin after BAL cells were collected. Samples were embedded in paraffin, sectioned, and stained with H&E.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To better define the nature of the infiltrating Th cells in the
murine model of asthma, we used intracellular cytokine staining and
flow cytometry to analyze the phenotype of CD4+ T cells in
the BAL and lung parenchyma over time following airway challenge. Mice
received primary and booster immunizations with i.p. injections of OVA
adsorbed to alum in PBS. Control animals were treated with alum alone
in PBS. The mice were then challenged on day 0 and day 6 with an
aerosol of 1% OVA in PBS. Control mice were challenged with an aerosol
of PBS alone. After challenge, mice were sacrificed and BAL fluid and
lung tissues were collected. Intracellular IFN- and IL-4 or IL-5 in
BAL cells and purified lung parenchymal T cells were analyzed by flow
cytometry.
The total numbers of inflammatory cells increased with time and with
repeated challenges in the airways of mice challenged with 1% OVA but
not saline (Fig. 1A). The
inflammatory cells contained both Th1 and Th2 cells, as defined by
intracellular IFN- and IL-4 staining, respectively (Fig. 1, B and C). Similar results were obtained in three
separate experiments. The data were also similar when IL-5 staining was
used as a Th2 marker. Interestingly, Th1 cells predominated early in
the development of inflammation, but Th2 cells predominated later.
Also, the fraction of CD4+ cells that was producing Th1 or
Th2 cytokines was larger in BAL than in the cells recovered from lung
tissue (Fig. 1C). This result suggests that
cytokine-producing cells are preferentially recruited to the airways
compared with the parenchyma.
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To investigate whether altering the relative balance of
Ag-specific Th1 and Th2 cells in mice could modulate the airway
inflammatory response, we passively transferred 25 or 5 million DO11
Th1 or Th2 cells into naive BALB/c female mice. The mice were then
sensitized and boosted with i.p. injections of OVA adsorbed to alum 14
and 7 days before challenge. On day 0, the mice were challenged with an
aerosol of 1% OVA in PBS for 20 min in the morning and afternoon. On
day 3, the mice were sacrificed and BAL fluid, lung tissue, and serum
were collected. OVA-sensitized and -challenged mice showed increased
levels of serum IgE above unchallenged controls, although the levels
were lower in recipients of transferred Th1 cells (OVA-specific IgE
levels by ELISA were: unsensitized mice, 0.01 arbitrary units (AU);
recipients of 25 x 106 Th1 cells, 0.08 AU; sensitized
controls, 0.20 AU, recipients of 25 x 106 Th2 cells,
0.17 AU). OVA-challenged mice showed accumulation of inflammatory cells
in both the perivascular and subepithelial regions, but the
inflammation in the recipients of OVA-specific Th1 cells was much more
severe (Fig. 2). This result was
accompanied by dramatically increased numbers of cells recovered by BAL
from mice that had received Th1 cells (Fig. 3), whereas mice that received Th2 cells
showed total cell numbers indistinguishable from controls.
Passively transferred Th2 cells failed to mobilize an inflammatory
response in the lungs or airways even when as many as 108
Th2 cells were transferred (data not shown). The largest increases of
infiltrating cells in mice that received Th1 cells were in the
lymphocyte and monocyte compartments (Table I). Interestingly, the average number of
eosinophils increased as well. Although this increase did not reach
statistical significance in this experiment, a trend toward increased
numbers of eosinophils was observed in similar experiments, and
eosinophils were clearly visible in the lung tissue as demonstrated by
eosinophil peroxidase staining and Biebrich scarlet staining (data not
shown). In mice that received Th2 cells, the only significant change
was a modest decrease in infiltrating lymphocytes. Similar data were
obtained in four separate experiments. Thus, transfer of OVA-specific
Th1 cells increased the airway inflammation whereas transfer of Th2
cells had little effect.
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, but very few were positive for IL-4 or IL-5
(Fig. 4
). In contrast, <1% of the Th2
cells stained for IFN-, whereas 43% were IL-4 positive and 35%
were IL-5 positive. After transfer and airway challenge, transgenic
(KJ1–26+) Th1 and Th2 cells were easily detected in the
BAL of recipient mice, indicating that both Th1 and Th2 populations
could persist in vivo for the length of the protocol, although the
total number of transferred Th1 cells recovered was much higher than
the number of Th2 cells (Fig. 5). When
transgenic Th1 cells were infused, less than 2% of the recovered
KJ1–26+ cells expressed IL-4. Conversely, when transgenic
Th2 cells were transferred, less than 2% of the recovered
KJ1–26+ cells expressed IFN- (Fig. 6, A–C).
Therefore, both Th1 and Th2 phenotypes appeared to be stable in vivo
throughout the course of the experiments.
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, D–F). Of interest, infusion of transgenic Th1
cells resulted in increased accumulation of host Th1 cells relative to
host Th2 cells in the airways (Figs. 6, D–F, and
7A). However, this did not result in fewer absolute numbers
of Th2 cells in the lungs of these mice. Rather, the absolute number of
Th2 cells actually increased in Th1 recipients relative to controls
(Fig. 7B).
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To test whether Ag-specific Th1 or Th2 cells could alter the
allergic inflammatory infiltrate in the airway of an already challenged
mouse, we immunized and challenged BALB/c female mice to establish
airway inflammation, and 1 day later passively transferred DO11 Th1 or
Th2 cells. On the next day, the mice were rechallenged and then
sacrificed 3 days later. Addition of Ag-specific Th1 cells early in the
course of an airway inflammatory response lead to increased
inflammation whereas addition of Th2 cells had little effect (Fig. 8A). In mice treated with Th1
cells, the total numbers of lymphocytes and macrophages increased as
shown in Table II. The average number of
eosinophils also increased although this did not reach statistical
significance in any of three separate experiments
(p = 0.10, 0.06, and 0.20). Similar to
Figs. 5–7, both transferred and host derived BAL CD4+ T cells
were analyzed by flow cytometry. Both transferred Th1 and Th2 cells
were detected in the BAL, and both maintained their original phenotype.
Again infusion of Th1 cells resulted in a dramatic increase in
recruitment of host Th1 cells, and a lesser increase in the recruitment
of host Th2 cells (Fig. 8B). Transferring Th2 cells had
little effect, except in one experiment of three in which transferring
50 x 106 Th2 cells resulted in a 50% decrease in
total inflammatory cell recruitment (data not shown).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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mRNA. Similarly, Bentley et al. 8 used
immunohistochemistry and in situ hybridization to evaluate cytokine
production in human bronchial mucosa after allergen challenge. Airway
challenge induced increases in mRNA for IL-5 and granulocyte-macrophage
CSF, and to a lesser extent IL-4 and IL-2, but again IFN- mRNA was
not increased. However, other data suggest an inductive role for Th1
cells. For example, in a study using intracellular cytokine staining to
evaluate BAL T cell cytokine profiles, asthmatic patients had increased
numbers of IFN--producing T cells compared with nonasthmatic
controls 23 . In this study, increased numbers of IL-4-producing T
cells were not observed. Also, asthma attacks resulting in visits to
hospitals are more likely to be associated with viral respiratory
infections, presumably usually enhancing Th1 cytokine production, than
with exposure to allergens 2 .
Similarly, in mouse models of asthma, the majority of the data supports
a critical role for Th2 cells, whereas the role of Th1 cells remains
less well defined. At the level of cytokine expression, the Th2
cytokines IL-4 and IL-5 have each been shown to be important. Mice
rendered IL-4-deficient either by gene targeting or by administration
of neutralizing anti-IL-4 Abs fail to develop either eosinophilic
inflammation or airway hyper-reactivity after allergen sensitization
and challenge 17, 18, 19 . Similarly, IL-5 knockout mice develop neither
eosinophilic inflammation nor airway hyper-reactivity 16 . Additional
studies have analyzed the role of cytokines from T cells. Using DO11 T
cells differentiated in vitro in a fashion similar to ours, Cohn et al.
30 showed that unsensitized mice that received OVA-specific Th2 cells
followed by daily aerosol challenges for 7–10 days developed lung
inflammation characterized by eosinophilia and mucus over-production.
Mice that received OVA-specific Th1 cells developed lung
inflammation dominated by neutrophils and lymphocytes and without
mucus over-production. In another study, Corry et al. 17
demonstrated using enzymatically dispersed lung tissue and an ELISPOT
assay that both IL-4- and IFN--producing cells were increased after
challenge of sensitized animals.
In the studies described here, we tested the potential roles of Th1
and Th2 cells in the OVA-induced model of allergic inflammation. We
used intracellular cytokine staining to demonstrate that both Th1 and
Th2 cells are recruited to the lung in the OVA model of experimental
asthma. Although the percentage of total inflammatory cells that
express Th2 cytokines increases as a function of time and with
successive challenges, Th1 cells remain in significant numbers. The
technique of intracellular cytokine staining is particularly useful in
that it can relatively rapidly offer cytokine analyses at the single
cell level and with limited possibility for cloning artifacts. It
thereby provides a "snapshot" of a T cell population at any given
time. However, the technique has some limitations. In particular, it is
not easy to determine whether the cytokines detected are the products
of cells responding in an Ag-specific fashion. To accumulate easily
detectable quantities of cytokine within cells, it is necessary to
culture them in vitro for several hours in PMA, ionomycin, and
monensin. This is thought not to induce Th phenotype differentiation,
but rather to elicit increased cytokine production and accumulation
from already committed cells; however, increased cytokine production is
expected to occur in all Th cells regardless of their Ag specificity.
In our experiments, it seems likely that many of the cells in the
airway are OVA-specific. We base this judgment on results shown in Fig. 1C in which the T cells recruited to the airways contain a
higher proportion of cytokine-producing cells than the parenchymal T
cells, and also on experiments with passively transferred cells in
which OVA-specific Th1 and Th2 cells were both enriched in the BAL
compared with the lung parenchyma. However, it remains a possibility
that mature Th1 and Th2 cells are recruited more efficiently than
undifferentiated cells regardless of their Ag specificity.
Other investigators have tried to modulate allergic responses with the
Th1-promoting cytokines, IL-12 and IFN-. Using sheep RBCs as the Ag,
Gavett et al. 21 showed that intratracheal and i.p. administration of
IL-12 at the time of challenge reduced airway hyper-reactivity and
eosinophilia. This coincided with an increase in IFN- and a decrease
in IL-4 mRNA and protein as measured by RT-PCR using total lung RNA
and by ELISA using BAL fluid. IL-5 levels were also reduced. In a
system of aerosol sensitization and challenge with OVA, Lack et al.
22 showed that nebulized IFN- could decrease OVA-specific IgE and
prevent airway hyper-reactivity even when the IFN- was administered
after sensitization. Furthermore, CD4+ T cells from IFN-
treated mice were able to inhibit IgE production in vitro.
In these studies, we have additionally tested the ability of
transferred Th1 and Th2 cells to modulate the allergic inflammatory
response in the airway. Our results show clearly that addition of
Ag-specific Th2 cells had little effect on the airway inflammatory
response, but that addition of Ag-specific Th1 cells dramatically
increased the inflammatory response. This was regardless of whether
the cells were transferred before sensitization or after challenge.
By gating specifically on endogenous cells in our FACS analysis,
we were able to monitor the effect of the transferred cells on the
host T cell response. Transferred Th1 cells promoted increased-host Th1
responses (Figs. 7, A and B, and 8B)
and partially inhibited OVA-specific IgE production; however, the
proinflammatory properties of the Th1 cells apparently outweighed any
counter-regulatory effects they may have on Th2 cells, and the end
result of transferring Th1 cells was that increased numbers of host
cells were recruited to the lung. These data argue that in studies
using IFN- and IL-12 to inhibit airway inflammation, the
inhibition seen was not mediated solely by the promotion of Th1
responses. Both IFN- and IL-12 are pleotropic cytokines and could be
altering airway inflammation via several different mechanisms that
might involve CD8+ T cells, NK cells, and/or macrophages.
It is curious that transferring Th2 cells did not increase the number
of eosinophils in the Ag-induced inflammatory response. In fact, the
only observable effect that the Th2 cells had was to decrease the
number of lymphocytes recruited to the BAL. The transferred Th2 cells
survive in the recipient animal over the course of the experiment (Fig. 5), and they are still capable of producing cytokines (Fig. 6C). Although it remains possible that transferred Th2 cells
could have greater effects on the inflammatory response at later time
points after challenge, our data suggest more simply that the
generation of Th2 cells may not be rate limiting for the development of
eosinophilic inflammation in this model. Perhaps the i.p. sensitization
with OVA and alum is sufficiently efficient in generating host Th2
cells that a maximal Th2 effect has already been elicited and that the
addition of exogenous Th2 cells cannot increase the response above this
maximum. This might also explain the differences between our data and
those of Cohn et al. 30 . In their system, passive transfer of Th2
cells into unsensitized animals followed by multiple airway challenges
resulted in airway eosinophilia whereas transfer of naive T cells
followed by the same airway challenge protocol resulted in no
inflammation. This suggested that the aerosol challenges were
inefficient at priming naive T cells.
In summary, we have shown that both Th1 and Th2 cells are recruited to the lung in the OVA-induced mouse model of asthma. Passively transferred OVA-specific Th1 cells can neither prevent the development of a Th2 response nor extinguish an established Th2 response. In fact, transfer of Th1 cells results in increased inflammation. This finding indicates that Th1 cells are inefficient at inhibiting Th2 responses in vivo, and that in this model the proinflammatory effects of Th1 cells outweigh any counter-regulatory effects they may have on the inflammatory response. These results further suggest a possible mechanism for the role of viral respiratory infections in triggering asthma attacks. In this setting, proinflammatory cytokines from virus-specific T cells could cooperate with allergen-specific Th2 cells without inhibiting them to increase the eosinophilic airway inflammatory reaction. These results also raise a warning flag regarding certain proposed immunotherapies for asthma, because therapies designed to enhance Th1 responses may actually increase airway inflammation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. David D. Chaplin, Howard Hughes Medical Institute and Department of Internal Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, Box 8022, St. Louis, MO 63110. E-mail address:
3 Abbreviations used in this paper: BAL, bronchoalveolar lavage; H&E, hematoxylin and eosin; PE, phycoerythrin.
Received for publication July 23, 1998. Accepted for publication November 5, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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knock out the Th2 hypothesis for asthma?. Am. J. Respir. Cell Mol. Biol. 14:316.[Medline]
ß T-cell-receptor transgenic system. Proc. Natl. Acad. Sci. USA 89:6065. receptor have impaired ability to resolve a lung eosinophilic inflammatory response associated with a prolonged capacity of T cells to exhibit a Th2 cytokine profile. J. Immunol. 156:2680.[Abstract]
inhibits the development of secondary allergic responses in mice. J. Immunol. 157:1432.[Abstract]
but is partially independent of IL-12. J. Immunol. 155:3427.[Abstract]
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A. Joetham, K. Takada, C. Taube, N. Miyahara, S. Matsubara, T. Koya, Y.-H. Rha, A. Dakhama, and E. W. Gelfand Naturally Occurring Lung CD4+CD25+ T Cell Regulation of Airway Allergic Responses Depends on IL-10 Induction of TGF-beta J. Immunol., February 1, 2007; 178(3): 1433 - 1442. [Abstract] [Full Text] [PDF]
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I. Meyts, P. W. Hellings, G. Hens, B. M. Vanaudenaerde, B. Verbinnen, H. Heremans, P. Matthys, D. M. Bullens, L. Overbergh, C. Mathieu, et al. IL-12 Contributes to Allergen-Induced Airway Inflammation in Experimental Asthma J. Immunol., November 1, 2006; 177(9): 6460 - 6470. [Abstract] [Full Text] [PDF]
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 E Hothersall, C McSharry, and N C Thomson Potential therapeutic role for statins in respiratory disease. Thorax, August 1, 2006; 61(8): 729 - 734. [Abstract] [Full Text] [PDF]
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C. S. Bakshi, M. Malik, P. M. Carrico, and T. J. Sellati T-bet Deficiency Facilitates Airway Colonization by Mycoplasma pulmonis in a Murine Model of Asthma J. Immunol., August 1, 2006; 177(3): 1786 - 1795. [Abstract] [Full Text] [PDF]
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J. W. Hollingsworth, G. S. Whitehead, K. L. Lin, H. Nakano, M. D. Gunn, D. A. Schwartz, and D. N. Cook TLR4 Signaling Attenuates Ongoing Allergic Inflammation J. Immunol., May 15, 2006; 176(10): 5856 - 5862. [Abstract] [Full Text] [PDF]
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M. R. King, A. S. Ismail, L. S. Davis, and D. R. Karp Oxidative stress promotes polarization of human T cell differentiation toward a T helper 2 phenotype. J. Immunol., March 1, 2006; 176(5): 2765 - 2772. [Abstract] [Full Text] [PDF]
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M. S. Leino, H. T. Alenius, N. Fyhrquist-Vanni, H. J. Wolff, K. E. Reijula, E.-L. Hintikka, M. S. Salkinoja-Salonen, T. Haahtela, and M. J. Makela Intranasal Exposure to Stachybotrys chartarum Enhances Airway Inflammation in Allergic Mice Am. J. Respir. Crit. Care Med., March 1, 2006; 173(5): 512 - 518. [Abstract] [Full Text] [PDF]
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 R. Fischer, J. R. McGhee, H. L. Vu, T. P. Atkinson, R. J. Jackson, D. Tome, and P. N. Boyaka Oral and Nasal Sensitization Promote Distinct Immune Responses and Lung Reactivity in a Mouse Model of Peanut Allergy Am. J. Pathol., December 1, 2005; 167(6): 1621 - 1630. [Abstract] [Full Text] [PDF]
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 S. Gandini, A. B. Lowenfels, E. M. Jaffee, T. D. Armstrong, and P. Maisonneuve Allergies and the Risk of Pancreatic Cancer: A Meta-analysis with Review of Epidemiology and Biological Mechanisms Cancer Epidemiol. Biomarkers Prev., August 1, 2005; 14(8): 1908 - 1916. [Abstract] [Full Text] [PDF]
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J. R. Gordon, F. Li, A. Nayyar, J. Xiang, and X. Zhang CD8{alpha}+, but Not CD8{alpha}-, Dendritic Cells Tolerize Th2 Responses via Contact-Dependent and -Independent Mechanisms, and Reverse Airway Hyperresponsiveness, Th2, and Eosinophil Responses in a Mouse Model of Asthma J. Immunol., August 1, 2005; 175(3): 1516 - 1522. [Abstract] [Full Text] [PDF]
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M. J. Walter and M. J. Holtzman A Centennial History of Research on Asthma Pathogenesis Am. J. Respir. Cell Mol. Biol., June 1, 2005; 32(6): 483 - 489. [Full Text] [PDF]
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A. J. M. van Oosterhout and A. C. Motta Th1/Th2 paradigm: not seeing the forest for the trees? Eur. Respir. J., April 1, 2005; 25(4): 591 - 593. [Full Text] [PDF]
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K. Irifune, A. Yokoyama, K. Sakai, A. Watanabe, H. Katayama, H. Ohnishi, H. Hamada, M. Nakajima, N. Kohno, and J. Higaki Adoptive transfer of T-helper cell type 1 clones attenuates an asthmatic phenotype in mice Eur. Respir. J., April 1, 2005; 25(4): 653 - 659. [Abstract] [Full Text] [PDF]
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T. Yasumi, K. Katamura, I. Okafuji, T. Yoshioka, T.-a. Meguro, R. Nishikomori, T. Kusunoki, T. Heike, and T. Nakahata Limited Ability of Antigen-Specific Th1 Responses to Inhibit Th2 Cell Development In Vivo J. Immunol., February 1, 2005; 174(3): 1325 - 1331. [Abstract] [Full Text] [PDF]
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 H. Hata, T. Yoshimoto, N. Hayashi, T. Hada, and K. Nakanishi IL-18 together with anti-CD3 antibody induces human Th1 cells to produce Th1- and Th2-cytokines and IL-8 Int. Immunol., December 1, 2004; 16(12): 1733 - 1739. [Abstract] [Full Text] [PDF]
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E. W. Gelfand, A. Joetham, Z.-H. Cui, A. Balhorn, K. Takeda, C. Taube, and A. Dakhama Induction and Maintenance of Airway Responsiveness to Allergen Challenge Are Determined at the Age of Initial Sensitization J. Immunol., July 15, 2004; 173(2): 1298 - 1306. [Abstract] [Full Text] [PDF]
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S. L. Kimzey, P. Liu, and J. M. Green Requirement for CD28 in the Effector Phase of Allergic Airway Inflammation J. Immunol., July 1, 2004; 173(1): 632 - 640. [Abstract] [Full Text] [PDF]
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M. Castro, S. R. Bloch, M. V. Jenkerson, S. DeMartino, D. L. Hamilos, R. B. Cochran, X. E. L. Zhang, H. Wang, J. P. Bradley, K. B. Schechtman, et al. Asthma Exacerbations after Glucocorticoid Withdrawal Reflects T Cell Recruitment to the Airway Am. J. Respir. Crit. Care Med., April 1, 2004; 169(7): 842 - 849. [Abstract] [Full Text] [PDF]
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E. A. B. Kelly and W. W. Busse Who Is Captain of the Inflammatory Ship in Asthma? Am. J. Respir. Crit. Care Med., March 1, 2004; 169(5): 551 - 552. [Full Text] [PDF]
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A. McKay, B. P. Leung, I. B. McInnes, N. C. Thomson, and F. Y. Liew A Novel Anti-Inflammatory Role of Simvastatin in a Murine Model of Allergic Asthma J. Immunol., March 1, 2004; 172(5): 2903 - 2908. [Abstract] [Full Text] [PDF]
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 T. Sugimoto, Y. Ishikawa, T. Yoshimoto, N. Hayashi, J. Fujimoto, and K. Nakanishi Interleukin 18 Acts on Memory T Helper Cells Type 1 to Induce Airway Inflammation and Hyperresponsiveness in a Naive Host Mouse J. Exp. Med., February 17, 2004; 199(4): 535 - 545. [Abstract] [Full Text] [PDF]
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H.-S. Kang, S. E. Blink, R. K. Chin, Y. Lee, O. Kim, J. Weinstock, T. Waldschmidt, D. Conrad, B. Chen, J. Solway, et al. Lymphotoxin Is Required for Maintaining Physiological Levels of Serum IgE That Minimizes Th1-mediated Airway Inflammation J. Exp. Med., December 1, 2003; 198(11): 1643 - 1652. [Abstract] [Full Text] [PDF]
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H. Matsue, D. Edelbaum, D. Shalhevet, N. Mizumoto, C. Yang, M. E. Mummert, J. Oeda, H. Masayasu, and A. Takashima Generation and Function of Reactive Oxygen Species in Dendritic Cells During Antigen Presentation J. Immunol., September 15, 2003; 171(6): 3010 - 3018. [Abstract] [Full Text] [PDF]
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M. B. Hogan, D. N. Weissman, A. F. Hubbs, L. F. Gibson, D. Piktel, and K. S. Landreth Regulation of Eosinophilopoiesis in a Murine Model of Asthma J. Immunol., September 1, 2003; 171(5): 2644 - 2651. [Abstract] [Full Text] [PDF]
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 A.-S. Charbonnier, H. Hammad, P. Gosset, G. A. Stewart, S. Alkan, A.-B. Tonnel, and J. Pestel Der p 1-pulsed myeloid and plasmacytoid dendritic cells from house dust mite-sensitized allergic patients dysregulate the T cell response J. Leukoc. Biol., January 1, 2003; 73(1): 91 - 99. [Abstract] [Full Text] [PDF]
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R. Stephens, D. A. Randolph, G. Huang, M. J. Holtzman, and D. D. Chaplin Antigen-Nonspecific Recruitment of Th2 Cells to the Lung as a Mechanism for Viral Infection-Induced Allergic Asthma J. Immunol., November 15, 2002; 169(10): 5458 - 5467. [Abstract] [Full Text] [PDF]
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R. Stephens and D. D. Chaplin IgE Cross-Linking or Lipopolysaccharide Treatment Induces Recruitment of Th2 Cells to the Lung in the Absence of Specific Antigen J. Immunol., November 15, 2002; 169(10): 5468 - 5476. [Abstract] [Full Text] [PDF]
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H. Matsue, C. Yang, K. Matsue, D. Edelbaum, M. Mummert, and A. Takashima Contrasting Impacts of Immunosuppressive Agents (Rapamycin, FK506, Cyclosporin A, and Dexamethasone) on Bidirectional Dendritic Cell-T Cell Interaction During Antigen Presentation J. Immunol., October 1, 2002; 169(7): 3555 - 3564. [Abstract] [Full Text] [PDF]
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 A Fukushima, K Fukata, A Ozaki, M Takata, N Kuroda, H Enzan, and H Ueno Exertion of the suppressive effects of IFN-{gamma} on experimental immune mediated blepharoconjunctivitis in Brown Norway rats during the induction phase but not the effector phase Br J Ophthalmol, October 1, 2002; 86(10): 1166 - 1171. [Abstract] [Full Text] [PDF]
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B. D. Medoff, A. Sauty, A. M. Tager, J. A. Maclean, R. N. Smith, A. Mathew, J. H. Dufour, and A. D. Luster IFN-{gamma}-Inducible Protein 10 (CXCL10) Contributes to Airway Hyperreactivity and Airway Inflammation in a Mouse Model of Asthma J. Immunol., May 15, 2002; 168(10): 5278 - 5286. [Abstract] [Full Text] [PDF]
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H. P. Jones, L. Tabor, X. Sun, M. D. Woolard, and J. W. Simecka Depletion of CD8+ T Cells Exacerbates CD4+ Th Cell-Associated Inflammatory Lesions During Murine Mycoplasma Respiratory Disease J. Immunol., April 1, 2002; 168(7): 3493 - 3501. [Abstract] [Full Text] [PDF]
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N. W. Lukacs, A. Berlin, D. Schols, R. T. Skerlj, and G. J. Bridger AMD3100, a CxCR4 Antagonist, Attenuates Allergic Lung Inflammation and Airway Hyperreactivity Am. J. Pathol., April 1, 2002; 160(4): 1353 - 1360. [Abstract] [Full Text] [PDF]
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H. Akiba, J. Kehren, M.-T. Ducluzeau, M. Krasteva, F. Horand, D. Kaiserlian, F. Kaneko, and J.-F. Nicolas Skin Inflammation During Contact Hypersensitivity Is Mediated by Early Recruitment of CD8+ T Cytotoxic 1 Cells Inducing Keratinocyte Apoptosis J. Immunol., March 15, 2002; 168(6): 3079 - 3087. [Abstract] [Full Text] [PDF]
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J. W. Verbsky, D. A. Randolph, L. P. Shornick, and D. D. Chaplin Nonhematopoietic Expression of Janus Kinase 3 Is Required for Efficient Recruitment of Th2 Lymphocytes and Eosinophils in OVA-Induced Airway Inflammation J. Immunol., March 1, 2002; 168(5): 2475 - 2482. [Abstract] [Full Text] [PDF]
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C. A. Byersdorfer and D. D. Chaplin Visualization of Early APC/T Cell Interactions in the Mouse Lung Following Intranasal Challenge J. Immunol., December 15, 2001; 167(12): 6756 - 6764. [Abstract] [Full Text] [PDF]
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 J. Liu, B. E. Anderson, M. E. Robert, J. M. McNiff, S. G. Emerson, W. D. Shlomchik, and M. J. Shlomchik Selective T-cell subset ablation demonstrates a role for T1 and T2 cells in ongoing acute graft-versus-host disease: a model system for the reversal of disease Blood, December 1, 2001; 98(12): 3367 - 3375. [Abstract] [Full Text] [PDF]
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S. S. SALVI, K. SURESH BABU, and S. T. HOLGATE Is Asthma Really Due to a Polarized T Cell Response Toward a Helper T Cell Type 2 Phenotype? Am. J. Respir. Crit. Care Med., October 15, 2001; 164(8): 1343 - 1346. [Full Text] [PDF]
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H. P. Jones, L. M. Hodge, K. Fujihashi, H. Kiyono, J. R. McGhee, and J. W. Simecka The Pulmonary Environment Promotes Th2 Cell Responses After Nasal-Pulmonary Immunization with Antigen Alone, but Th1 Responses Are Induced During Instances of Intense Immune Stimulation J. Immunol., October 15, 2001; 167(8): 4518 - 4526. [Abstract] [Full Text] [PDF]
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D. D'AMBROSIO, M. MARIANI, P. PANINA-BORDIGNON, and F. SINIGAGLIA Chemokines and Their Receptors Guiding T Lymphocyte Recruitment in Lung Inflammation Am. J. Respir. Crit. Care Med., October 1, 2001; 164(7): 1266 - 1275. [Full Text] [PDF]
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A. Takaoka, Y. Tanaka, T. Tsuji, T. Jinushi, A. Hoshino, Y. Asakura, Y. Mita, K. Watanabe, S. Nakaike, Y. Togashi, et al. A Critical Role for Mouse CXC Chemokine(s) in Pulmonary Neutrophilia During Th Type 1-Dependent Airway Inflammation J. Immunol., August 15, 2001; 167(4): 2349 - 2353. [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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D. M. Walter, C. P. Wong, R. H. DeKruyff, G. J. Berry, S. Levy, and D. T. Umetsu IL-18 Gene Transfer by Adenovirus Prevents the Development of and Reverses Established Allergen-Induced Airway Hyperreactivity J. Immunol., May 15, 2001; 166(10): 6392 - 6398. [Abstract] [Full Text] [PDF]
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 L. M. Hodge, M. Marinaro, H. P. Jones, J. R. McGhee, H. Kiyono, and J. W. Simecka Immunoglobulin A (IgA) Responses and IgE-Associated Inflammation along the Respiratory Tract after Mucosal but Not Systemic Immunization Infect. Immun., April 1, 2001; 69(4): 2328 - 2338. [Abstract] [Full Text] [PDF]
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J.C. Kips, K.G. Tournoy, and R.A. Pauwels New anti-asthma therapies: suppression of the effect of interleukin (IL)-4 and IL-5 Eur. Respir. J., March 1, 2001; 17(3): 499 - 506. [Abstract] [Full Text] [PDF]
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 W. W. Busse and R. F. Lemanske Asthma N. Engl. J. Med., February 1, 2001; 344(5): 350 - 362. [Full Text] [PDF]
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S.-s. J. Sung, C. E. Rose Jr., and S. M. Fu Intratracheal Priming with Ovalbumin- and Ovalbumin 323-339 Peptide-Pulsed Dendritic Cells Induces Airway Hyperresponsiveness, Lung Eosinophilia, Goblet Cell Hyperplasia, and Inflammation J. Immunol., January 15, 2001; 166(2): 1261 - 1271. [Abstract] [Full Text] [PDF]
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Z. Peng, H. Wang, X. Mao, K. T. HayGlass, and F. E. R. Simons CpG oligodeoxynucleotide vaccination suppresses IgE induction but may fail to down-regulate ongoing IgE responses in mice Int. Immunol., January 1, 2001; 13(1): 3 - 11. [Abstract] [Full Text] [PDF]
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T.-J. Huang, P. A. MacAry, P. Eynott, A. Moussavi, K. C. Daniel, P. W. Askenase, D. M. Kemeny, and K. F. Chung Allergen-Specific Th1 Cells Counteract Efferent Th2 Cell-Dependent Bronchial Hyperresponsiveness and Eosinophilic Inflammation Partly Via IFN-{{gamma}} J. Immunol., January 1, 2001; 166(1): 207 - 217. [Abstract] [Full Text] [PDF]
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D. C. Tsitoura, S. Kim, K. Dabbagh, G. Berry, D. B. Lewis, and D. T. Umetsu Respiratory Infection with Influenza A Virus Interferes with the Induction of Tolerance to Aeroallergens J. Immunol., September 15, 2000; 165(6): 3484 - 3491. [Abstract] [Full Text] [PDF]
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C. A. JONES and P. G. HOLT Immunopathology of Allergy and Asthma in Childhood Am. J. Respir. Crit. Care Med., August 1, 2000; 162(2): S36 - 39. [Full Text] [PDF]
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P. G. KNOTT, P. R. GATER, and C. P. BERTRAND Airway Inflammation Driven by Antigen-specific Resident Lung CD4+ T Cells in alpha beta -T Cell Receptor Transgenic Mice Am. J. Respir. Crit. Care Med., April 1, 2000; 161(4): 1340 - 1348. [Abstract] [Full Text]
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M. Castro, D. D. Chaplin, M. J. Walter, and M. J. Holtzman Could Asthma Be Worsened by Stimulating the T-helper Type 1 Immune Response? Am. J. Respir. Cell Mol. Biol., February 1, 2000; 22(2): 143 - 146. [Full Text]
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 D. A. Randolph, G. Huang, C. J. Carruthers, L. E. Bromley, and D. D. Chaplin The Role of CCR7 in TH1 and TH2 Cell Localization and Delivery of B Cell Help in Vivo Science, December 10, 1999; 286(5447): 2159 - 2162. [Abstract] [Full Text]
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D. T. Umetsu and R. H. DeKruyff Interleukin-10 . The Missing Link in Asthma Regulation? Am. J. Respir. Cell Mol. Biol., November 1, 1999; 21(5): 562 - 563. [Full Text]
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L. Cohn, R. J. Homer, N. Niu, and K. Bottomly T Helper 1 Cells and Interferon {gamma} Regulate Allergic Airway Inflammation and Mucus Production J. Exp. Med., November 1, 1999; 190(9): 1309 - 1318. [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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H. Xie, Y.-C. Lim, F. W. Luscinskas, and A. H. Lichtman Acquisition of Selectin Binding and Peripheral Homing Properties by CD4+ and CD8+ T Cells J. Exp. Med., June 7, 1999; 189(11): 1765 - 1776. [Abstract] [Full Text] [PDF]
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