| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
*
Division of Basic Sciences, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206;
The Jackson Laboratory, Bar Harbor, ME 04609; and
Max-Planck-Institut für Immunbiologie, Freiburg, Germany
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, results in airway hyperresponsiveness (AHR) and
eosinophil influx into the airways, both of which are prevented by
pretreatment with anti-IL-5 Ab. To delineate the role of IL-5,
IL-4, and IFN- in the development of RSV-induced AHR and lung
eosinophilia, we tested the ability of mice deficient in each of these
cytokines to develop these symptoms of RSV infection. Mice deficient in
either IL-5, IL-4, or IFN- were administered infectious RSV
intranasally, and 6 days later, airway responsiveness to inhaled
methacholine was assessed by barometric body plethysmography, and
numbers of lung eosinophils and production of IFN-, IL-4, and IL-5
by mononuclear cells from peribronchial lymph nodes were monitored. RSV
infection resulted in airway eosinophilia and AHR in both IL-4- and
IFN--deficient mice, but not in IL-5-deficient mice. Reconstitution
of IL-5-deficient mice with IL-5 restored these responses and enhanced
the responses in IL-4-deficient mice. Anti-VLA-4 (very late Ag-4)
treatment prevented lung eosinophilia and AHR following RSV infection
and IL-5 reconstitution. We conclude that in response to RSV, IL-5 is
essential for the influx of eosinophils into the lung and that
eosinophils in turn are critical for the development of AHR. IFN-
and IL-4 are not essential for these responses to RSV
infection. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
in the development of virus-induced AHR, we assessed
in the present study the ability of mice deficient in IL-5, IL-4, or
IFN- to develop inflammatory airway responses and AHR to MCh
following RSV infection. In addition, to define the role of airway
eosinophils in the development of AHR, we utilized a mAb to the
4 integrin subunit of the very late Ag (VLA)-4. VLA-4 is
expressed on eosinophils and other circulating leukocytes, except
neutrophils, and binds to VCAM-1 on endothelial cells 9, 10 . In vitro
studies demonstrated that VLA-4 interaction with VCAM-1 results in
adhesion to endothelium and transendothelial migration 9, 11 .
Anti-VLA-4 Ab has previously been shown to inhibit eosinophil
recruitment to the lung in murine models of allergic airway
inflammation 12, 13 . |
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Female IL-5-sufficient or IL-5-deficient C57BL/6 mice from our
colony (initially derived at Max-Planck-Institut for Immunology,
Freiburg, Germany), IL-4-sufficient and IL-4-deficient, and
IFN--sufficient and IFN--deficient BALB/c mice (The Jackson
Laboratory, Bar Harbor, ME), all 8 to 16 wk of age and free of specific
pathogens, were used in this study. All animals used in this study were
under a protocol approved by the Institutional Animal Care and Use
Committee of the National Jewish Medical and Research Center.
Virus
Human RSV, group A (Long strain), free of chlamydia or mycoplasma contamination, was obtained from the Viral Diagnostics Laboratory, Health Sciences Center, University of Colorado (Denver, CO). The virus was cultured on Hep 2 cells from American Type Culture Collection (ATCC, Manassas, VA) in medium containing FCS from Life Technologies (Grand Island, NY). It was purified as described 14 . Briefly, cells and supernatant were harvested, the cells were disrupted by ultrasonic manipulation, and the suspension was clarified by centrifugation (8000 x g, 20 min). The supernatant was layered over 30% sucrose in STEU buffer (0.1 M sodium chloride, 0.01 M Tris, 0.001 M EDTA, and 1 M urea, all obtained from Sigma, St. Louis, MO) and centrifuged (100,000 x g, 1 h, 10°C). The pellet was resuspended in 1.2 ml PBS, aliquoted, and frozen at -70°C. The suspension was adjusted to contain 4 x 106 PFU of RSV/ml, as assessed by quantitative plaque-forming assay.
Infection of mice
Mice were infected under light anesthesia (2.5% Avertin, 0.015 ml/g body weight) by intranasal inoculation of RSV (105 PFU in 50 µl PBS). Controls were sham infected with PBS in the same way. Efficacy of this infection procedure was regularly tested by qualitative plaque-forming assays 15 : briefly, on day 4 postinfection, mice were sacrificed; the lungs were removed, homogenized, and centrifuged; and the supernatant was added to Hep 2 cell cultures. Infection could be demonstrated by cell pathogenic effects in all infected animals tested, but not in mice sham infected with PBS.
Experimental protocols
Mice were infected on day 0. Airway responsiveness to MCh was
assessed on day 6 postinfection and animals were sacrificed the
following day for the removal of peribronchial lymph nodes (PBLN) and
lungs. In a separate set of experiments, IL-5-deficient and
IL-4-deficient mice were reconstituted with 40 ng of murine IL-5
(kindly provided by Dr. James Lee, Mayo Clinic, Scottsdale, AZ) given
i.v. on days 0, 2, and 4 after RSV infection or following sham
infection. Additionally, on days 2 and 4 postinfection, some
RSV-infected and IL-5-reconstituted IL-5-deficient mice were treated
i.v. with 100 µg of anti-VLA-4 (4 chain) Ab (rat IgG2b)
isolated from supernatants of PS/2 cells obtained from ATCC or with rat
IgG2b as a control.
Determination of airway responsiveness
Airway responsiveness was assessed using a single chamber whole body plethysmograph obtained from Buxco (Troy, NY), as described 16 . In this system, a spontaneously breathing mouse is placed into the main chamber of the plethysmograph, and pressure differences between this chamber and a reference chamber are recorded. The resulting box pressure signal is caused by volume and resultant pressure changes during the respiratory cycle of the animal. From these box pressure signals the phases of the respiratory cycle, tidal volumes, and enhanced pause (Penh) can be calculated. Penh is a dimensionless value that represents the function of the proportion of maximal expiratory to maximal inspiratory box pressure signals and the timing of expiration. It correlates closely with pulmonary resistance measured by conventional two-chamber plethysmography in ventilated animals 16 and was used as a measure of airway responsiveness in this study. In the plethysmograph, mice were exposed for 3 min to nebulized PBS and subsequently to increasing concentrations of nebulized MCh (Sigma) in PBS using an AeroSonic ultrasonic nebulizer (DeVilbiss, Somerset, PA). After each nebulization, recordings were taken for 3 min. The Penh values measured during each 3-min sequence were averaged and are expressed for each MCh concentration as the percentage of baseline Penh values following PBS exposure.
Lung and bone marrow cell isolation
Lung cells were isolated by collagenase digestion, as previously described 17 , and counted with a hemocytometer. Bone marrow from the right femur was collected by saline irrigation. Cells from either preparation were counted with a hemocytometer. Cytospin slides were stained with Leukostat from Fisher Diagnostics (Pittsburgh, PA), and differential cell counts were performed in a blinded fashion by counting at least 300 cells under light microscopy.
Cell preparation
PBLN were harvested and mononuclear cells were purified by passing the tissue through a stainless steel mesh, followed by density-gradient centrifugation (Organon Teknika, Durham, NC). Cells were washed three times with PBS and resuspended in RPMI 1640 medium (Life Technologies, Gaithersburg, MD).
In vitro cytokine production
Mononuclear cells were cultured for 48 h in 96-well
round-bottom plates at a concentration of 400,000 cells/well in the
absence or presence of UV-inactivated RSV (equivalent of
104 PFU/well) or the combination of ionomycin (0.5 µM)
from Calbiochem (La Jolla, CA) and phorbol 12, 13-dibutyrate (10 ng/ml;
Sigma). Supernatants were harvested and frozen at -20°C. The
concentrations of IFN-, IL-4, and IL-5 in the supernatants were
assessed by ELISA, as described 18 . Briefly, Immulon-2 plates from
Dynatech Laboratories (Chantilly, VA) were coated with anti-IFN-
(R4-6A2; PharMingen, San Diego, CA), anti-IL-4 (11B11; PharMingen),
or anti-IL-5 Abs (TRFK-5; Dr. R. Coffman) and blocked with PBS/10%
FCS overnight. Samples were added; biotinylated anti-IFN- (XMG
1.2; PharMingen), anti-IL-4 (BVD6-24G2; PharMingen), or
anti-IL-5 Abs (TRFK-4; PharMingen) were used as detecting Abs; and
the reactions were amplified with avidin-horseradish-peroxidase
(Sigma). Cytokine levels were calculated by comparison with known
cytokine standards (PharMingen). The limit of detection in the assay
was 4 pg/ml for each cytokine.
Statistical analysis
Pairs of groups were compared by Student’s t test; comparison of more than two groups was performed by the Tukey-Kramer HSD test. Values of p were deemed significant at 0.05. Values for all measurements are expressed as the mean ± SD, except for values of airway responsiveness (Penh), which are expressed as the mean ± SEM.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
IL-5-deficient or IL-5-sufficient mice were infected by intranasal
instillation of RSV (105 PFU). The airway response to MCh
in mice infected with RSV and in sham-infected controls was assessed by
barometric whole body plethysmography on day 6 after RSV inoculation.
The airways of IL-5-sufficient mice infected with RSV were
significantly more reactive than the airways of sham-infected controls
(Fig. 1
A). Penh to 100 mg/ml
MCh increased 4.2 ± 0.6-fold over PBS in infected mice compared
with a 2.2 ± 0.2-fold increase in mice sham infected with PBS. In
contrast, in IL-5-deficient mice, acute RSV infection did not result in
increased airway responsiveness to MCh.
|
To investigate changes in numbers of pulmonary inflammatory cells
during acute RSV infection, lung cells were isolated and differential
cell counts were performed. In IL-5-sufficient mice acutely infected
with RSV, the numbers of eosinophils and neutrophils were significantly
increased in lung cell isolates compared with sham-infected controls
(Fig. 1
B). The increases in numbers of eosinophils and
neutrophils were 4.5- and 1.6-fold, respectively. The total numbers of
isolated lung cells did not differ significantly between the groups. In
contrast, in IL-5-deficient mice, no increase in numbers of pulmonary
eosinophils could be observed, but RSV infection still resulted in
increased numbers of neutrophils in the lung.
Acute RSV infection causes an increase in IFN-, but not in IL-5
production in IL-5-deficient mice
We measured the production of IFN-, IL-4, and IL-5 in 48-h
cultures of mononuclear cells obtained from PBLN, harvested on day 7
postinfection, and stimulated with UV-inactivated RSV or phorbol
dibutyrate/ionomycin. In IL-5-sufficient mice, production of IFN-
and IL-5 was significantly increased following RSV infection (Table I). In IL-5-deficient mice on the other
hand, no IL-5 could be detected, but RSV infection still resulted in
increased IFN- production. Indeed, in IL-5-deficient mice, IFN-
levels were higher than in IL-5-sufficient mice. Only very low levels
of IL-4 were detected in any of the groups.
|
IL-5-deficient mice infected with RSV or sham infected
were reconstituted with IL-5. In sham-infected mice, this treatment
resulted in increases in numbers of eosinophils in the bone marrow
(from 0.14 ± 0.10 to 0.45 ± 0.14 x 106
eosinophils/femur, p < 0.05, both n =
6), but not in the lung, and airway responsiveness to MCh was not
increased. In contrast, in RSV-infected IL-5-deficient mice,
reconstitution with IL-5 not only resulted in bone marrow eosinophilia
(from 0.16 ± 0.11 to 0.66 ± 0.16 x 106
eosinophils/femur, p < 0.05, both n =
6), but also in eosinophil influx to the lung (Fig. 2b) and in the development of
AHR to MCh (Fig. 2a). The Penh to 100 mg/ml MCh increased
5.8 ± 2.7-fold over PBS in this group of animals.
|
RSV-infected IL-5-deficient mice were reconstituted with IL-5 and
at the same time treated with anti-VLA-4 Ab or rat IgG2b as a
control. Treatment with anti-VLA-4, but not with rat IgG, prevented
increases in numbers of lung eosinophils (Fig. 2B) and the
development of AHR to MCh observed in RSV-infected IL-5-deficient mice
following IL-5 reconstitution (Fig. 2C).
RSV infection in IFN--deficient mice results in increased IL-5
production, eosinophil influx into the lung, and AHR to MCh
IFN--sufficient and IFN--deficient BALB/c mice were infected
intranasally with RSV. On day 6 of the acute infection, airway
responsiveness to MCh was assessed, and on day 7 lung inflammatory
cells were enumerated. RSV infection in both IFN--deficient and
IFN--sufficient mice resulted in AHR to MCh (Fig. 3A) and in increases in
numbers of lung eosinophils and neutrophils (Fig. 3B).
Compared with IFN--sufficient mice, the dose-response curve to MCh
was shifted to the left, and the influx of eosinophils into the lung
was greater in IFN--deficient mice following RSV infection.
Furthermore, RSV infection resulted in increases in IL-5 and IL-4
production in PBLN cell cultures of IFN--deficient mice (Table II). In contrast, in IFN--sufficient
BALB/c mice, decreases in IL-4 and IL-5 production were observed
following RSV infection (IL-4, from 71 ± 24.7 to 10.8 ±
1.6 pg/ml; IL-5, from 1996.3 ± 536.7 to 686 ±
322.8 pg/ml; both p < 0.05, n = 12).
|
|
IL-4-deficient and IL-4-sufficient BALB/c mice were infected
intranasally with RSV, and some IL-4-deficient mice were treated with
IL-5 during the infection. Airway responsiveness to MCh was assessed on
day 6 postinfection, and on day 7 lung inflammatory cells were counted.
RSV infection resulted in AHR to MCh (Fig. 4A) and in increases in
numbers of lung eosinophils and neutrophils (Fig. 4B) in
both IL-4-deficient and IL-4-sufficient mice. In IL-4-deficient mice,
the numbers of eosinophils and neutrophils were similar to the numbers
in the IL-4-sufficient mice, but in deficient mice the dose-response
curve to MCh was shifted to the right, and maximal Penh values,
although not significantly different, were about 40% lower than in
IL-4-sufficient mice. In the IL-4-deficient mice, RSV infection
resulted in increases in IFN-, but not in IL-5 production in PBLN
cell cultures (Table II). In IL-4-sufficient BALB/c mice, RSV infection
led to a decrease in IL-5 production in culture (IL-5, from 1448.6
± 916.8 to 394.5 ± 384.2 pg/ml, p < 0.05,
n = 12), but IL-5 production in both infected and
uninfected animals exceeded the maximal IL-5 production in
IL-4-deficient mice (72.5 ± 56.3 pg/ml). Treatment of
IL-4-deficient mice with IL-5 during RSV infection further augmented
airway responsiveness to MCh and further increased the influx of
eosinophils (but not neutrophils) into the lung in response to RSV
(Fig. 4, A and B).
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
dependent,
and 2) whether AHR is dependent on the influx of eosinophils to the
airways under these conditions. To address these issues, we compared
the responses to RSV infection in IL-5-, IL-4-, and IFN--deficient
mice. Airway responsiveness to aerosolized MCh was assessed using
barometric whole body plethysmography in unrestrained animals, and
pulmonary inflammation and cytokine production in the local draining
lymph nodes of the lung, the PBLN, were monitored.
Acute RSV infection in IL-5-sufficient C57BL/6 mice resulted in
significant increases in airway responsiveness to MCh, and this was
associated with the infiltration of both eosinophils and neutrophils in
the lung. These findings parallel those seen in BALB/c mice 8, 19 and
in other models of respiratory tract viral infection 20 . As has been
reported previously 21 and in our studies of allergic sensitization
of the airways, altered airway responsiveness to MCh develops to a
lower degree and at higher concentrations of the bronchoconstrictor in
C57BL/6 mice compared with BALB/c mice. This was also seen following
RSV infection (Figs. 1, 3, and 4). Assessment of cytokine production by
mononuclear cells from the PBLN during acute RSV infection in
IL-5-sufficient C57BL/6 mice demonstrated that both IFN- and IL-5
production were increased. The increases in IFN- production during
acute RSV infection are in keeping with observations made earlier that
showed increased production of total IFN in tracheobroncheal lavages
from RSV-infected mice 22 , and with our own observations in BALB/c
mice that exhibited an increase in IFN- following RSV infection 8 .
In BALB/c mice, IL-5 production was decreased compared with noninfected
controls, but RSV-infected BALB/c mice still produced substantial
amounts of IL-5 8 . C57BL/6 mice are less prone to develop Th2
responses than are BALB/c mice 23, 24 . This may explain the lower
levels of IL-4 detected in noninfected and RSV-infected mice of this
strain. In contrast to the sufficient mice, IL-5-deficient mice did not
develop pulmonary eosinophilia or AHR following RSV infection. This was
not due to a lack of infection since RSV infection in the lungs could
be demonstrated by plaque-forming assay (data not shown) and resulted
in an influx of neutrophils into the lung and increased production of
IFN- in these animals. Indeed, the number of neutrophils and the
levels of IFN- were higher in IL-5-deficient than in
IL-5-sufficient mice. These observations extend our previous
findings that anti-IL-5 Ab treatment reduces influx of eosinophils,
but not of neutrophils to the lung, and prevents the development of AHR
8 . These data suggest that the lack of IL-5 is the critical element
that prevents eosinophilic airway inflammation and the development of
AHR during RSV infection in these deficient mice. If so, then
administration of IL-5 should render IL-5-deficient mice susceptible to
the effects of RSV infection, and this was the case. Reconstitution of
IL-5-deficient mice with IL-5 during RSV infection resulted in
increases in numbers of eosinophils in the bone marrow, eosinophil
influx into the lung, and the development of AHR. These consequences of
IL-5 treatment were all dependent on RSV infection, except for the bone
marrow eosinophilia that also occurred in sham-infected, IL-5-deficient
mice reconstituted with IL-5. These data demonstrate that IL-5 is
essential for the influx of eosinophils and for the development of AHR
in response to RSV infection and, in turn, the absence of IL-5 appeared
protective against the development of AHR. To delineate whether IL-5
itself is directly responsible for the development of increased airway
responsiveness or whether the eosinophils that are recruited to the
lung during RSV infection in the presence of IL-5 are themselves
necessary for the development of AHR, we treated RSV-infected,
IL-5-reconstituted, IL-5-deficient mice with anti-VLA-4 Ab. The
adhesion molecule VLA-4, expressed on eosinophils and other circulating
lymphocytes except neutrophils 9 , is known to be important in the
recruitment of mononuclear cells and eosinophils from the circulation
to sites of inflammation 11, 12, 13 . In the present study, anti-VLA-4
treatment prevented the influx of eosinophils into the lung and the
development of AHR in infected and reconstituted IL-5-deficient mice.
This indicates that eosinophil recruitment to the lung is essential for
the development of RSV-induced AHR. One could argue that the inhibition
of AHR by anti-VLA-4 treatment might also be due to impaired
recruitment of lymphocytes that may secrete IL-5 or result in AHR by
some other mechanism, e.g., IL-11 secretion 25 . Given that
anti-VLA-4 treatment was effective even following administration of
IL-5, the lack of IL-5 secretion by lymphocytes cannot be the
explanation for the inhibition of AHR. Furthermore, if non-IL-5- or
noneosinophil-mediated mechanisms were primarily responsible for the
development of RSV-induced AHR, one would have expected to observe AHR
following RSV infection in IL-5-deficient mice that are otherwise
immunologically competent.
Using genetically deficient BALB/c mice, we also tested whether
RSV-induced AHR is dependent on the cytokines IFN- or IL-4. The Th1
cytokine IFN- is produced in large amounts during acute RSV
infection in humans 26 and in mice 8, 21, 27 . It may play a pivotal
role in virus-induced inflammation 28 . Increased amounts of IFN-
have been observed in cells from bronchoalveolar lavage (BAL) of atopic
asthmatics 29, 30 . The role of IFN- in the development of
allergen-induced AHR remains controversial. On one hand, administration
of IFN- during airway sensitization has been shown to inhibit
allergic airway inflammation and AHR 31, 32 . On the other hand, in a
study employing an Ab against IFN-, this cytokine seemed to play a
critical role in the development of allergen-induced AHR 33 . The role
of IFN- in virus-induced AHR was investigated in the present study:
RSV infection resulted in eosinophil and neutrophil influx into the
lung and AHR in IFN--deficient mice. Interestingly,
IFN--deficient mice developed AHR at lower MCh concentrations and
recruited more eosinophils to the lung than IFN--sufficient
controls. Furthermore, IL-4 and IL-5 production was increased following
RSV infection in IFN--deficient mice. In IFN--sufficient BALB/c
mice, RSV infection resulted in a decrease in the production of IL-4
and IL-5. These observations show that IFN- is not necessary for the
development of RSV-induced lung eosinophilia and AHR. Furthermore, the
data suggest that the presence of IFN- may be somewhat protective
against these consequences of RSV infection, possibly by preventing
excessive production of Th2 type cytokines.
The Th2 cytokine IL-4 has been implicated in the development of allergic asthma. Increased levels of IL-4 in BAL fluid 34 and increased expression of IL-4 mRNA in BAL cells 35 and bronchial biopsies 36 have been demonstrated in patients with atopic asthma. In murine models of allergic airway sensitization, IL-4 has been found to be crucial for the development of allergic airway inflammation 37, 38 and AHR 39, 40 in some studies, while others demonstrated a partial inhibition of eosinophil recruitment to the lung, but no inhibition of AHR or histologic damage of the airways in IL-4-deficient mice 41 . IL-4 may be involved in the development of allergic asthma via several mechanisms, some of which may be of importance in RSV-induced AHR as well. IL-4 is necessary for the production of allergen-specific IgE 42, 43 , which in turn may be critical for the development of AHR by activation of mast cells 44 and eosinophils 45 . RSV-specific IgE may play a role in the development of bronchiolitis and asthma following RSV infection in infants 46 . Furthermore, IL-4 is known to be involved in up-regulation of VCAM-1 on vascular endothelial cells 9 , facilitating eosinophil and lymphocyte extravasation; IL-4 is also involved in Th2 cell recruitment to sites of allergic inflammation 47 . As we show in the present study, increased eosinophil recruitment is essential in RSV-induced AHR, as previously shown for allergen-induced AHR. RSV infection in IL-4-deficient mice resulted in recruitment of eosinophils and neutrophils to the lung and in development of AHR. Although numbers of lung eosinophils did not differ significantly between IL-4-sufficient and IL-4-deficient mice, increases in airway responsiveness were considerably smaller in IL-4-deficient mice. In addition, in IL-4-deficient animals, only very low levels of IL-5 were detected following RSV infection. Treatment of IL-4-deficient mice with IL-5 during infection resulted in a significant increase in airway responsiveness and in eosinophil influx when compared with untreated mice. These data suggest that although IL-4 may not be absolutely necessary for RSV-induced lung eosinophilia and AHR, it does contribute to the overall magnitude of AHR most likely through enhancing Th2 cell differentiation and enhanced IL-5 production.
In summary, we present a murine model of airway inflammation and AHR
following acute RSV infection. Utilizing mice deficient in either IL-5,
IL-4, or IFN-, we show that IL-5 is critical for the development of
RSV-induced lung eosinophilia and AHR, and that prevention of
eosinophil recruitment to the lungs by anti-VLA-4 attenuates AHR.
The presence of IL-4, while not essential, may enhance AHR in RSV
infection by enhancing IL-5 production. In contrast, IFN-, the
predominant cytokine in acute RSV infection, does not seem to be
required for the development of AHR, and in RSV-infected
IFN--deficient mice the eosinophilic inflammatory response and
airway responsiveness to inhaled MCh are enhanced.
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Erwin W. Gelfand, Department of Pediatrics, National Jewish Medical and Research Center, 1400 Jackson Street, Denver, CO 80206. E-mail address:
3 Abbreviations used in this paper: RSV, respiratory syncytial virus; AHR, airway hyperresponsiveness; BAL, bronchoalveolar lavage; MCh, methacholine; PBLN, peribronchial lymph nodes; PFU, plaque-forming unit; VLA, very late antigen.
Received for publication July 6, 1998. Accepted for publication December 1, 1998.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
4ß7 integrin mediates lymphocyte binding to the mucosal vascular addressing MAdCAM-1. Cell 74:185.[Medline]
4 integrins in vivo. J. Clin. Invest. 94:1722.
4 integrin) on intrapulmonary but not circulating leukocytes inhibits airway inflammation and hyperresponsiveness in a mouse model. J. Clin. Invest. 100:3038.
). Curr. Opin. Immunol. 9:17.[Medline]
and interferon- by bronchoalveolar leukocytes from patients with bronchial asthma. Am. Rev. Respir. Dis. 147:291.[Medline]
decreases IgE production and normalizes airway function in a murine model of allergen sensitization. J. Immunol. 152:2546.[Abstract]
gene transfer inhibits pulmonary allergic responses in mice. J. Immunol. 157:3216.[Abstract]
and independent of eosinophil infiltration. Am. J. Respir. Cell Mol. Biol. 16:325.[Abstract]
) cytokines in bronchoalveolar lavage and bronchial biopsies from atopic asthmatics and normal control subjects. Am. J. Respir. Cell Mol. Biol. 12:477.[Abstract]
transcripts in B lymphoid cells. J. Exp. Med. 168:2385. transcripts in human B cells induced by interleukin-4 to switch to IgE production. J. Exp. Med. 172:463.This article has been cited by other articles:
|
|
 |
|
  G. Zhang, J. Rowe, M. Kusel, A. Bosco, K. McKenna, N. de Klerk, P. D. Sly, and P. G. Holt Interleukin-10/Interleukin-5 Responses at Birth Predict Risk for Respiratory Infections in Children with Atopic Family History Am. J. Respir. Crit. Care Med., February 1, 2009; 179(3): 205 - 211. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 T. Kobayashi, Y. Takaku, A. Yokote, H. Miyazawa, T. Soma, K. Hagiwara, M. Kanazawa, and M. Nagata Interferon-{beta} augments eosinophil adhesion-inducing activity of endothelial cells Eur. Respir. J., December 1, 2008; 32(6): 1540 - 1547. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Kolli, E. L. Bataki, L. Spetch, A. Guerrero-Plata, A. M. Jewell, P. A. Piedra, G. N. Milligan, R. P. Garofalo, and A. Casola T Lymphocytes Contribute to Antiviral Immunity and Pathogenesis in Experimental Human Metapneumovirus Infection J. Virol., September 1, 2008; 82(17): 8560 - 8569. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. S. Mohapatra and S. Boyapalle Epidemiologic, Experimental, and Clinical Links between Respiratory Syncytial Virus Infection and Asthma Clin. Microbiol. Rev., July 1, 2008; 21(3): 495 - 504. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 N. Nisar, R. Guleria, S. Kumar, T. Chand Chawla, and N. Ranjan Biswas Mycoplasma pneumoniae and its role in asthma Postgrad. Med. J., February 1, 2007; 83(976): 100 - 104. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Wang, N. Peters, and J. Schwarze Plasmacytoid Dendritic Cells Limit Viral Replication, Pulmonary Inflammation, and Airway Hyperresponsiveness in Respiratory Syncytial Virus Infection J. Immunol., November 1, 2006; 177(9): 6263 - 6270. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. A. Herd, S. Mahalingam, I. M. Mackay, M. Nissen, T. P. Sloots, and R. W. Tindle Cytotoxic T-Lymphocyte Epitope Vaccination Protects against Human Metapneumovirus Infection and Disease in Mice J. Virol., February 15, 2006; 80(4): 2034 - 2044. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Miller, C. Gerard, M. Schaller, A. D. Gruber, A. A. Humbles, and N. W. Lukacs Deletion of CCR1 Attenuates Pathophysiologic Responses during Respiratory Syncytial Virus Infection J. Immunol., February 15, 2006; 176(4): 2562 - 2567. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Joetham, K. Takeda, C. Taube, N. Miyahara, A. Kanehiro, A. Dakhama, and E. W. Gelfand Airway Hyperresponsiveness in the Absence of CD4+ T Cells after Primary but Not Secondary Challenge Am. J. Respir. Cell Mol. Biol., July 1, 2005; 33(1): 89 - 96. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Teske, A. A. Bohn, J. F. Regal, J. J. Neumiller, and B. P. Lawrence Activation of the aryl hydrocarbon receptor increases pulmonary neutrophilia and diminishes host resistance to influenza A virus Am J Physiol Lung Cell Mol Physiol, July 1, 2005; 289(1): L111 - L124. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Matheson, V. J. Johnson, and M. I. Luster Immune Mediators in a Murine Model for Occupational Asthma: Studies with Toluene Diisocyanate Toxicol. Sci., March 1, 2005; 84(1): 99 - 109. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. M. Matheson, V. J. Johnson, V. Vallyathan, and M. I. Luster Exposure and Immunological Determinants in a Murine Model for Toluene Diisocyanate (TDI) Asthma Toxicol. Sci., March 1, 2005; 84(1): 88 - 98. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J Schwarze and U Schauer Enhanced virulence, airway inflammation and impaired lung function induced by respiratory syncytial virus deficient in secreted G protein Thorax, June 1, 2004; 59(6): 517 - 521. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. J. Easton, J. B. Domachowske, and H. F. Rosenberg Animal Pneumoviruses: Molecular Genetics and Pathogenesis Clin. Microbiol. Rev., April 1, 2004; 17(2): 390 - 412. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. M. Bramley, M. A. Khan, H. E. Manson, and R. G. Hegele Development of Respiratory Syncytial Virus "Bronchiolitis" in Guinea Pigs Does Not Reflect an Allergic Predisposition in the Host Chest, August 1, 2003; 124(2): 671 - 681. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Wohlleben, J. Muller, U. Tatsch, C. Hambrecht, U. Herz, H. Renz, E. Schmitt, H. Moll, and K. J. Erb Influenza A Virus Infection Inhibits the Efficient Recruitment of Th2 Cells into the Airways and the Development of Airway Eosinophilia J. Immunol., May 1, 2003; 170(9): 4601 - 4611. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. L. Lambert, J. B. Mangum, M. P. DeLorme, and J. I. Everitt Ultrafine Carbon Black Particles Enhance Respiratory Syncytial Virus-Induced Airway Reactivity, Pulmonary Inflammation, and Chemokine Expression Toxicol. Sci., April 1, 2003; 72(2): 339 - 346. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Raman, M. H. Kaplan, C. M. Hogaboam, A. Berlin, and N. W. Lukacs STAT4 Signal Pathways Regulate Inflammation and Airway Physiology Changes in Allergic Airway Inflammation Locally Via Alteration of Chemokines J. Immunol., April 1, 2003; 170(7): 3859 - 3865. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. R. Johnson, R. A. Parker, J. E. Johnson, and B. S. Graham IL-13 Is Sufficient for Respiratory Syncytial Virus G Glycoprotein-Induced Eosinophilia After Respiratory Syncytial Virus Challenge J. Immunol., February 15, 2003; 170(4): 2037 - 2045. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. A. Bonville, A. J. Easton, H. F. Rosenberg, and J. B. Domachowske Altered Pathogenesis of Severe Pneumovirus Infection in Response to Combined Antiviral and Specific Immunomodulatory Agents J. Virol., December 20, 2002; 77(2): 1237 - 1244. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
V. del Pozo, M. Rojo, M. L. Rubio, I. Cortegano, B. Cardaba, S. Gallardo, M. Ortega, E. Civantos, E. Lopez, C. Martin-Mosquero, et al. Gene Therapy with Galectin-3 Inhibits Bronchial Obstruction and Inflammation in Antigen-challenged Rats through Interleukin-5 Gene Downregulation Am. J. Respir. Crit. Care Med., September 1, 2002; 166(5): 732 - 737. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. B. Domachowske, C. A. Bonville, A. J. Easton, and H. F. Rosenberg Pulmonary eosinophilia in mice devoid of interleukin-5 J. Leukoc. Biol., June 1, 2002; 71(6): 966 - 972. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Schwarze and E.W. Gelfand Respiratory viral infections as promoters of allergic sensitization and asthma in animal models Eur. Respir. J., February 1, 2002; 19(2): 341 - 349. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. Wennergren and S. Kristjansson Relationship between respiratory syncytial virus bronchiolitis and future obstructive airway diseases Eur. Respir. J., December 1, 2001; 18(6): 1044 - 1058. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K-;H. Carlsen and P.J. Sterk Infection: friend or foe to the development of asthma? Eur. Respir. J., November 1, 2001; 18(5): 744 - 747. [Full Text] [PDF]
|
|
|
|
|
|
C. M. Fleming, H. He, A. Ciota, D. Perkins, and P. W. Finn Administration of Pentoxifylline During Allergen Sensitization Dissociates Pulmonary Allergic Inflammation from Airway Hyperresponsiveness J. Immunol., August 1, 2001; 167(3): 1703 - 1711. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. W. Lukacs, K. K. Tekkanat, A. Berlin, C. M. Hogaboam, A. Miller, H. Evanoff, P. Lincoln, and H. Maassab Respiratory Syncytial Virus Predisposes Mice to Augmented Allergic Airway Responses Via IL-13-Mediated Mechanisms J. Immunol., July 15, 2001; 167(2): 1060 - 1065. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
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]
|
|
|
|
|
|
H. A. Haeberle, W. A. Kuziel, H.-J. Dieterich, A. Casola, Z. Gatalica, and R. P. Garofalo Inducible Expression of Inflammatory Chemokines in Respiratory Syncytial Virus-Infected Mice: Role of MIP-1{alpha} in Lung Pathology J. Virol., January 15, 2001; 75(2): 878 - 890. [Abstract] [Full Text]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 T. Ikemura, J. Schwarze, M. Makela, A. Kanehiro, A. Joetham, K. Ohmori, and E. W. Gelfand Type 4 Phosphodiesterase Inhibitors Attenuate Respiratory Syncytial Virus-Induced Airway Hyper-Responsiveness and Lung Eosinophilia J. Pharmacol. Exp. Ther., August 1, 2000; 294(2): 701 - 706. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
