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CUTTING EDGE |
Sections of
*
Immunobiology and
Pulmonary and Critical Care Medicine, Yale University School of Medicine, New Haven, CT 06520;
Immunology Research, Genentech, Inc., South San Francisco, CA 94080; and
§
Howard Hughes Medical Institute, New Haven, CT 06536
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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and IL-4 and
IL-5-producing CD4 T cells have been identified in the airways of
asthmatics. After transfer of in vitro-generated TCR transgenic Th1 or
Th2 cells and exposure to inhaled Ag, Th2 cells induced AHR and airway
eosinophilia, whereas Th1 cells induced neutrophilic
inflammation without AHR. Next, to determine the precise effector
function of IL-4 in Th2 cell-induced AHR, we transferred
IL-4-/- Th2 cells into wild-type and
IL-4-/- recipient mice. After exposure to inhaled Ag,
both groups of mice exhibited AHR with markedly reduced airway
eosinophilia. Thus, IL-4 production by Th2 cells is not
essential for the induction of AHR, but is critical for the migration
of eosinophils from lung tissue into the
airways. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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secreting Th1-like cells (6, 7). In
sarcoidosis, a disease characterized by the presence of activated Th1
cells infiltrating the lung, AHR is often present (8, 9). Data from
animal models of allergic inflammation implicate a role for Th2 cells
in AHR; however, AHR has also been reported in animal models of
Th1-driven inflammation (10, 11). Thus, the role of Th1 or Th2 cells in
the induction of AHR has not been clearly defined. Priming naive CD4 T cells results in the generation of Th1 or Th2 effector cells. The cytokine environment in which a naive CD4 T cell is stimulated can determine its differentiative fate, such that T cells stimulated in the presence of IL-4 become Th2 cells, and those stimulated in the presence of IL-12 become Th1 cells. IL-4 is required for the generation of Th2 cells (12). Thus, studies delineating the role of IL-4 in both airway inflammation and AHR have been difficult, because in the absence of IL-4 there is defective Th2 cell priming as well as a subsequent loss of Th2 effector response.
To investigate the direct effect of Th1 and Th2 cells on AHR, we generated Th1 and Th2 cells in vitro from TCR transgenic CD4 T cells. We have previously shown that these populations of OVA-specific Th1 or Th2 effector cells, once transferred into recipient mice, can be activated in the lung after exposure to inhaled OVA, and their patterns of cytokine production persist in vivo (13). We showed that Th2 cells induced many of the histopathologic features of asthma, including airway eosinophilia and mucus hypersecretion, whereas Th1 cells induced airway neutrophilia and had no effect on mucus production. In this report we show that AHR is induced by Th2 cells, but not Th1 cells. To definitively assess the effector role of IL-4 in AHR, we generated IL-4-/- Th2 cells in vitro, transferred them into recipient mice, and exposed them to inhaled OVA. These data show that Th2 cells induce AHR in the absence of IL-4.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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Th1 or Th2 cells were generated from BALB/c DO11.10 or DO11
IL-4-/- mice, which are transgenic for the TCR
recognizing OVA peptide 323–339 (pOVA323–339) (Ref. 14;
kindly provided by K. Murphy, Washington University, St. Louis, MO).
DO11.10 CD4 T cells were isolated from splenocytes by negative
selection, and syngeneic T-depleted splenocytes were used as APCs and
treated with mitomycin-C as previously described (15). All cultures
were set up in flasks containing equal numbers of CD4 T cells and APCs
at a concentration of 0.5 x 106 cells/ml. To generate
Th1 cells, cultures contained pOVA323–339 (5 µg/ml),
IL-12 (5 ng/ml) (Genetics Institute, Cambridge, MA), and anti-IL-4
(11B11) at inhibitory concentration. To generate Th2 cells, cultures
contained pOVA323–339 (5 µg/ml), IL-4 (200 U/ml)
(Collaborative Research, Waltham, MA), and anti-IFN- (XMG1.2) at
inhibitory concentration. Cultured Th1 or Th2-like cells were harvested
after 4 days and washed with PBS, and 5 x 106 cells
were injected i.v. into syngeneic BALB/c or BALB/c
IL-4-/- recipients (The Jackson Laboratories, Bar Harbor,
ME). At the time of transfer, FACS (Becton Dickinson, Mountain View,
CA) analysis was performed on Th1 and Th2 cell preparations. The
transferred cell populations were determined to be >95% CD4 and TCR
transgene positive using anti-CD4 (Quantum Red-L3T4, Sigma, St.
Louis, MO), and DO11.10 TCR-specific, anti-clonotypic Ab, KJ1–26,
and fluorescein isothiocyanate-avidin D (Vector Laboratories,
Burlingame, CA). Beginning 1 day after transfer of cells, mice were
challenged for 20 min daily for 7 days with inhaled 1% OVA in PBS,
using an ultrasonic nebulizer (UltraAir NE-U07, OMRON, Vernon
Hills, IL) as previously described (13). Twenty-four hours after the
last exposure, mice were subjected to pulmonary function testing or
sacrificed for analysis of airway inflammation.
Bronchoalveolar lavage
BAL was performed by cannulation of the trachea and lavage with 1 ml of PBS. Cytospin preparations of BAL cells were stained with Dif-Quik (Baxter Healthcare, Miami, FL), and differentials were performed on 200 cells based on morphology and staining characteristics.
Cytokine assays
At the time of transfer, an aliquot of Th1- or Th2-like cells or
naive CD4 T cells were retained for restimulation. A total of 5 x
105 CD4 T cells/ml and 5 x 105/ml freshly
isolated BALB/c APCs were cultured with pOVA323–339 (5
µg/ml), and supernatants were collected at 48 h. ELISAs were
performed as previously described (13). The lower limit of sensitivity
for each of the ELISAs was 0.6 ng/ml (IFN-), 15 pg/ml (IL-4), 0.025
ng/ml (IL-5), 0.030 ng/ml (IL-13).
Lung physiology
Airway responsiveness to five doses of i.v. acetylcholine (ACh) (0.1–10 mg/kg) was determined. Mice were anesthetized (50 mg/kg pentobarbital, 1.8 g/kg urethane), intubated with a 20-gauge stainless steel catheter through which they were ventilated (Harvard Apparatus, Holliston, MA) with 100% O2 at a tidal volume of 9 µl/g at 150 breaths/min after paralysis with 0.5 mg/kg pancromonium bromide. A 27-gauge needle connected to a catheter was inserted into the tail veil for drug delivery before placement in a volume displacement body plethysmograph (Penn Century, Philadelphia, PA). Continuous measurements of airway pressure and thoracic flow were obtained using a computerized data acquisition system (Buxco Electronics, Sharon, CT), and pulmonary resistance was computed (16). Mean baseline and peak pulmonary resistance (±SE) after each dose was used for statistical analysis. ACh dose responses were analyzed by repeated measures analysis of variance.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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To investigate how different T cell subsets activated in the lung
effect AHR, Th1 and Th2 cells were generated from CD4 T cells isolated
from TCR transgenic DO11.10 mice and transferred into syngeneic
recipient mice as previously described (13). Consistent with our
previous findings, CD4 T cells stimulated to differentiate into Th1
cells produced high levels of IFN- and low to undetectable IL-4 and
IL-13, whereas the cells stimulated to differentiate into Th2 cells
secreted high levels of IL-4, IL-5, and IL-13 and minimal IFN- (Fig. 1
A). After transfer of cells,
mice were exposed to inhaled OVA or PBS. Mice that received Th1 or Th2
cells and inhaled OVA exhibited airway inflammation with similar number
of cells isolated by BAL, but the characteristics of the infiltrating
leukocytes were different. Neutrophilia was observed in mice that
received Th1 cells, whereas mice that received Th2 cells and inhaled
OVA had airway eosinophilia (Fig. 1B). Mice that
received Th1 or Th2 cells and inhaled PBS had no lung inflammation
(data not shown). Mice that received no cells and inhaled OVA showed no
inflammation, and BAL cells recovered showed differentials that were
similar to those of naive mice with >97% macrophages.
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). Therefore, once
activated in the airways, Th2 cells, but not Th1 cells, induce AHR.
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Th2 cells induce AHR in the absence of IL-4
IL-4 is a marker of Th2 cell activation in asthma. It has been
identified in BAL and biopsies of asthmatic patients (5, 18). However,
it has been difficult to dissect the effector function of IL-4 in
inflammation and AHR from its critical role in the generation of Th2
cells. Several lines of evidence indicate that when T cells are primed
in vivo in IL-4-deficient, IL-4R-deficient, or STAT6-deficient mice, or
during blockade with anti-IL-4 Ab, there is defective Th2 cell
generation (12, 19, 20, 21, 22, 23, 24, 25). Instead, Th1-predominant cell populations
result and are recruited to the lung after Ag challenge, and the
effects on airway inflammation and AHR often reflect the presence of
Th1 cells and IFN- (26, 27, 28) as much as the absence of IL-4. Thus,
when AHR was absent using these experimental systems, it was likely due
to a Th1-predominant response in the airways. Furthermore, in studies
in which IL-4 effects were blocked after priming of Th2 cells but
before Ag challenge, there is conflicting data with respect to
AHR (22, 24) and airway eosinophilia (22, 29, 30).
Because Th2 cells induced AHR when recruited and activated in the
respiratory tract, we looked specifically at the effector functions of
Th2 cells in the absence of IL-4. We generated Th2 cells from DO11.10
and DO11.10 IL-4-/- mice. Since, in the absence of IL-4,
Th2 cells are not generated, DO11.10 IL-4-/- CD4 cells
were stimulated with pOVA323–339 and APCs in the presence
of IL-4. At the time of transfer, Th2 cells from IL-4-/-
mice produced no IL-4, but secreted high levels of IL-5, IL-10, and
IL-13, and these cytokines were comparable to the levels secreted by
wild-type DO11.10 Th2 cells (Fig. 3A). Thus, equivalent
populations of Th2 cells were generated, with the exception of the
production of IL-4, and were transferred into wild-type BALB/c mice.
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B). In the absence of IL-4, Th2 cell
activation resulted in a marked reduction in BAL
eosinophils and a concomitant increase in neutrophils. FACS
staining on BAL with anti-CD4 and the anti-clonotypic Ab,
KJ1.26, showed that TCR transgenic CD4 T cells made up similar
percentages of the total cells, 9% (±0.7) in mice that received
wild-type Th2 and 11% (±2.2) in mice that received
IL-4-/- Th2 cells and inhaled OVA. Mucus production was
induced equally in mice that received wild-type Th2 or
IL-4-/- Th2 cells and inhaled OVA as previously shown
(13). These studies indicate that along with IL-5, which is known to be
essential for eosinophil recruitment to areas of
inflammation, IL-4 is critical for the development of BAL
eosinophilia.
Both mice that received wild-type or IL-4-/- Th2 cells
and inhaled OVA showed increased baseline pulmonary resistance compared
with mice that received no cells and aerosolized OVA (data not shown).
Responsiveness to i.v. ACh was increased in mice that received either
wild-type Th2 cells or IL-4-/- Th2 cells when compared
with mice that received no cells and inhaled OVA (Fig. 4). This finding was reproducible in both
wild-type and IL-4-/- recipient mice, thus eliminating
the possibility that endogenous cells in wild-type BALB/c recipient
mice could influence AHR. These data show that AHR is induced by Th2
cells in the complete absence of IL-4, and Th2 cell production of IL-4
is important for the development of BAL eosinophilia.
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Our previous studies with normal, nontransgenic OVA specific
IL-4-/- Th2 cells from BALB/c mice showed that in the
absence of IL-4, recruitment of inflammatory cells to the lung did not
occur and could be stimulated by exogenous administration of TNF-
(13). In the current studies, however, IL-4-/- TCR
transgenic cells from DO11.10 mice were recruited to the lung equally
well as shown by similar numbers of TCR transgenic cells in the BAL. We
believe that recruitment in the TCR transgenic system is due to a 10-
to 20-fold increase in cytokines produced by the transgenic Th2 cells.
We are currently investigating the cytokines involved in Th2 cell
recruitment to the lung in the TCR transgenic and nontransgenic
systems.
It remains unclear how Th2 cells control AHR. These data together with our previous studies show that Th2 cells directly induce multiple features of asthma; AHR, airway eosinophilia, and mucus hypersecretion. IL-4 has both local and systemic effects that relate to asthma and atopy, yet AHR can be induced in its absence. Eosinophilic inflammation following Th2 cell activation remains a possible mechanism of AHR. It is also possible that IL-13, which shares many of the biologic effects of IL-4, can stimulate AHR in its absence, or that IL-13 mediates AHR distinct from functions of IL-4.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. L. Cohn, Section of Immunobiology, Yale University School of Medicine, 333 Cedar Street, P.O. Box 208011, New Haven, CT 06520-8011. E-mail address:
3 Abbreviations used in this paper: AHR, airway hyperresponsiveness; BAL, bronchoalveolar lavage; pOVA323–339, OVA peptide 323–339; ACh, acetylcholine.
Received for publication June 24, 1998. Accepted for publication August 12, 1998.
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References |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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and interferon- by bronchoalveolar leukocytes from patients with bronchial asthma. Am. Rev. Respir. Dis. 147:291.[Medline]
) cytokines in bronchoalveolar lavage and bronchial biopsies from atopic asthmatic and normal control subjects. Am. J. Respir. Cell Mol. Biol. 12:477.[Abstract]
gene transfer inhibits pulmonary allergic responses in mice. J. Immunol. 157:3216.[Abstract]
decreases IgE production and normalizes airways function in a murine model of allergen sensitization. J. Immunol. 152:2546.[Abstract]
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C. Taube, C. Duez, Z.-H. Cui, K. Takeda, Y.-H. Rha, J.-W. Park, A. Balhorn, D. D. Donaldson, A. Dakhama, and E. W. Gelfand The Role of IL-13 in Established Allergic Airway Disease J. Immunol., December 1, 2002; 169(11): 6482 - 6489. [Abstract] [Full Text] [PDF]
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 J. V. Fahy Goblet Cell and Mucin Gene Abnormalities in Asthma Chest, December 1, 2002; 122(6_suppl): 320S - 326S. [Abstract] [Full Text] [PDF]
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L. Whittaker, N. Niu, U.-A. Temann, A. Stoddard, R. A. Flavell, A. Ray, R. J. Homer, and L. Cohn Interleukin-13 Mediates a Fundamental Pathway for Airway Epithelial Mucus Induced by CD4 T Cells and Interleukin-9 Am. J. Respir. Cell Mol. Biol., November 1, 2002; 27(5): 593 - 602. [Abstract] [Full Text] [PDF]
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J. M. Matheson, R. Lemus, R. W. Lange, M. H. Karol, and M. I. Luster Role of Tumor Necrosis Factor in Toluene Diisocyanate Asthma Am. J. Respir. Cell Mol. Biol., October 1, 2002; 27(4): 396 - 405. [Abstract] [Full Text] [PDF]
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A. M. Khan, O. Elidemir, C. E. Epstein, K. P. Lally, H. Xue, M. Blackburn, G. L. Larsen, and G. N. Colasurdo Meconium aspiration produces airway hyperresponsiveness and eosinophilic inflammation in a murine model Am J Physiol Lung Cell Mol Physiol, October 1, 2002; 283(4): L785 - L790. [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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S. J. Hirst, M. P. Hallsworth, Q. Peng, and T. H. Lee Selective Induction of Eotaxin Release by Interleukin-13 or Interleukin-4 in Human Airway Smooth Muscle Cells Is Synergistic with Interleukin-1beta and Is Mediated by the Interleukin-4 Receptor alpha -Chain Am. J. Respir. Crit. Care Med., April 15, 2002; 165(8): 1161 - 1171. [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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D. Sheppard Uses of Expression Microarrays in Studies of Pulmonary Fibrosis, Asthma, Acute Lung Injury, and Emphysema : Roger S. Mitchell Lecture Chest, March 1, 2002; 121(2007): 21S - 25S. [Abstract] [Full Text] [PDF]
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S. P. Chapoval, K. Iijima, E. V. Marietta, M. K. Smart, A. I. Chapoval, A. G. Andrews, and C. S. David Allergic Inflammatory Response to Short Ragweed Allergenic Extract in HLA-DQ Transgenic Mice Lacking CD4 Gene J. Immunol., January 15, 2002; 168(2): 890 - 899. [Abstract] [Full Text] [PDF]
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 S. Finotto, M. F. Neurath, J. N. Glickman, S. Qin, H. A. Lehr, F. H. Y. Green, K. Ackerman, K. Haley, P. R. Galle, S. J. Szabo, et al. Development of Spontaneous Airway Changes Consistent with Human Asthma in Mice Lacking T-bet Science, January 11, 2002; 295(5553): 336 - 338. [Abstract] [Full Text] [PDF]
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K. Blease, C. Jakubzick, J. M. Schuh, B. H. Joshi, R. K. Puri, and C. M. Hogaboam IL-13 Fusion Cytotoxin Ameliorates Chronic Fungal-Induced Allergic Airway Disease in Mice J. Immunol., December 1, 2001; 167(11): 6583 - 6592. [Abstract] [Full Text] [PDF]
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J. V. FAHY Remodeling of the Airway Epithelium in Asthma Am. J. Respir. Crit. Care Med., November 15, 2001; 164(10): S46 - 51. [Abstract] [Full Text] [PDF]
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H. Kishikawa, J. Sun, A. Choi, S.-C. Miaw, and I-C. Ho The Cell Type-Specific Expression of the Murine IL-13 Gene Is Regulated by GATA-3 J. Immunol., October 15, 2001; 167(8): 4414 - 4420. [Abstract] [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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M. Yang, S. P. Hogan, P. J. Henry, K. I. Matthaei, A. N. J. McKenzie, I. G. Young, M. E. Rothenberg, and P. S. Foster Interleukin-13 Mediates Airways Hyperreactivity through the IL-4 Receptor-Alpha Chain and STAT-6 Independently of IL-5 and Eotaxin Am. J. Respir. Cell Mol. Biol., October 1, 2001; 25(4): 522 - 530. [Abstract] [Full Text] [PDF]
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A. SUTO, H. NAKAJIMA, S.-I. KAGAMI, K. SUZUKI, Y. SAITO, and I. IWAMOTO Role of CD4+ CD25+ Regulatory T Cells in T Helper 2 Cell-mediated Allergic Inflammation in the Airways Am. J. Respir. Crit. Care Med., August 15, 2001; 164(4): 680 - 687. [Abstract] [Full Text] [PDF]
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 J-C Renauld New insights into the role of cytokines in asthma J. Clin. Pathol., August 1, 2001; 54(8): 577 - 589. [Abstract] [Full Text] [PDF]
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J. Mattes, M. Yang, A. Siqueira, K. Clark, J. MacKenzie, A. N. J. McKenzie, D. C. Webb, K. I. Matthaei, and P. S. Foster IL-13 Induces Airways Hyperreactivity Independently of the IL-4R{alpha} Chain in the Allergic Lung J. Immunol., August 1, 2001; 167(3): 1683 - 1692. [Abstract] [Full Text] [PDF]
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J.C. Kips Cytokines in asthma Eur. Respir. J., July 2, 2001; 18(34_suppl): 24S - 33s. [Abstract] [Full Text] [PDF]
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J. T. Chapman, L. E. Otterbein, J. A. Elias, and A. M. K. Choi Carbon monoxide attenuates aeroallergen-induced inflammation in mice Am J Physiol Lung Cell Mol Physiol, July 1, 2001; 281(1): L209 - L216. [Abstract] [Full Text] [PDF]
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A. Tomkinson, C. Duez, G. Cieslewicz, J. C. Pratt, A. Joetham, M.-C. Shanafelt, R. Gundel, and E. W. Gelfand A Murine IL-4 Receptor Antagonist That Inhibits IL-4- and IL-13-Induced Responses Prevents Antigen-Induced Airway Eosinophilia and Airway Hyperresponsiveness J. Immunol., May 1, 2001; 166(9): 5792 - 5800. [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. A. Wilder, D. S. Collie, D. E. Bice, Y. Tesfaigzi, C. R. Lyons, and M. F. Lipscomb Ovalbumin aerosols induce airway hyperreactivity in naive DO11.10 T cell receptor transgenic mice without pulmonary eosinophilia or OVA-specific antibody J. Leukoc. Biol., April 1, 2001; 69(4): 538 - 547. [Abstract] [Full Text]
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A. Nakata, O. Kaminuma, K. Ogawa, H. Fujimura, K. Fushimi, H. Kikkawa, K. Naito, K. Ikezawa, R. W. Egan, and A. Mori Correlation between eosinophilia induced by CD4+ T cells and bronchial hyper-responsiveness Int. Immunol., March 1, 2001; 13(3): 329 - 339. [Abstract] [Full Text] [PDF]
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A. TOMKINSON, G. CIESLEWICZ, C. DUEZ, K. A. LARSON, J. J. LEE, and E. W. GELFAND Temporal Association between Airway Hyperresponsiveness and Airway Eosinophilia in Ovalbumin-Sensitized Mice Am. J. Respir. Crit. Care Med., March 1, 2001; 163(3): 721 - 730. [Abstract] [Full Text] [PDF]
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 S. W. Chensue, N. W. Lukacs, T.-Y. Yang, X. Shang, K. A. Frait, S. L. Kunkel, T. Kung, M. T. Wiekowski, J. A. Hedrick, D. N. Cook, et al. Aberrant In Vivo T Helper Type 2 Cell Response and Impaired Eosinophil Recruitment in CC Chemokine Receptor 8 Knockout Mice J. Exp. Med., February 26, 2001; 193(5): 573 - 584. [Abstract] [Full Text] [PDF]
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L. Cohn, C. Herrick, N. Niu, R. J. Homer, and K. Bottomly IL-4 Promotes Airway Eosinophilia by Suppressing IFN-{{gamma}} Production: Defining a Novel Role for IFN-{{gamma}} in the Regulation of Allergic Airway Inflammation J. Immunol., February 15, 2001; 166(4): 2760 - 2767. [Abstract] [Full Text] [PDF]
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A. G.-H. Jember, R. Zuberi, F.-T. Liu, and M. Croft Development of Allergic Inflammation in a Murine Model of Asthma Is Dependent on the Costimulatory Receptor OX40 J. Exp. Med., February 5, 2001; 193(3): 387 - 392. [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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K. L. Denzler, S. C. Farmer, J. R. Crosby, M. Borchers, G. Cieslewicz, K. A. Larson, S. Cormier-Regard, N. A. Lee, and J. J. Lee Eosinophil Major Basic Protein-1 Does Not Contribute to Allergen-Induced Airway Pathologies in Mouse Models of Asthma J. Immunol., November 15, 2000; 165(10): 5509 - 5517. [Abstract] [Full Text] [PDF]
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J. Deng, V. P. Yeung, D. Tsitoura, R. H. DeKruyff, D. T. Umetsu, and S. Levy Allergen-Induced Airway Hyperreactivity Is Diminished in CD81-Deficient Mice J. Immunol., November 1, 2000; 165(9): 5054 - 5061. [Abstract] [Full Text] [PDF]
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J. Wang, R. J. Homer, Q. Chen, and J. A. Elias Endogenous and Exogenous IL-6 Inhibit Aeroallergen-Induced Th2 Inflammation J. Immunol., October 1, 2000; 165(7): 4051 - 4061. [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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J. C. KIPS, K. G. TOURNOY, and R. A. PAUWELS Gene Knockout Models of Asthma Am. J. Respir. Crit. Care Med., September 1, 2000; 162(3): S66 - 70. [Full Text] [PDF]
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J. Wang, R. J. Homer, L. Hong, L. Cohn, C. G. Lee, S. Jung, and J. A. Elias IL-11 Selectively Inhibits Aeroallergen-Induced Pulmonary Eosinophilia and Th2 Cytokine Production J. Immunol., August 15, 2000; 165(4): 2222 - 2231. [Abstract] [Full Text] [PDF]
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 L. H. Glimcher and K. M. Murphy Lineage commitment in the immune system: the T helper lymphocyte grows up Genes & Dev., July 15, 2000; 14(14): 1693 - 1711. [Full Text]
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D. C. Webb, A. N. J. McKenzie, A. M. L. Koskinen, M. Yang, J. Mattes, and P. S. Foster Integrated Signals Between IL-13, IL-4, and IL-5 Regulate Airways Hyperreactivity J. Immunol., July 1, 2000; 165(1): 108 - 113. [Abstract] [Full Text] [PDF]
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H. Matsuse, A. K. Behera, M. Kumar, H. Rabb, R. F. Lockey, and S. S. Mohapatra Recurrent Respiratory Syncytial Virus Infections in Allergen-Sensitized Mice Lead to Persistent Airway Inflammation and Hyperresponsiveness J. Immunol., June 15, 2000; 164(12): 6583 - 6592. [Abstract] [Full Text] [PDF]
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N. M. Munoz, G. A. van Seventer, R. T. Semnani, and A. R. Leff Augmentation of LTC4 synthesis in human eosinophils caused by CD3-stimulated Th2-like cells in vitro Am J Physiol Lung Cell Mol Physiol, June 1, 2000; 278(6): L1172 - L1179. [Abstract] [Full Text] [PDF]
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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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W. R. Henderson Jr., E. Y. Chi, and C. R. Maliszewski Soluble IL-4 Receptor Inhibits Airway Inflammation Following Allergen Challenge in a Mouse Model of Asthma J. Immunol., January 15, 2000; 164(2): 1086 - 1095. [Abstract] [Full Text] [PDF]
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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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L. Cohn, R. J. Homer, H. MacLeod, M. Mohrs, F. Brombacher, and K. Bottomly Th2-Induced Airway Mucus Production Is Dependent on IL-4R{alpha}, But Not on Eosinophils J. Immunol., May 15, 1999; 162(10): 6178 - 6183. [Abstract] [Full Text] [PDF]
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 I.-C. HO, J.I. KIM, S.J. SZABO, and L.H. GLIMCHER Tissue-specific Regulation of Cytokine Gene Expression Cold Spring Harb Symp Quant Biol, January 1, 1999; 64(0): 573 - 584. [Abstract] [PDF]
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