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Division of Immunology and Transplantation Biology, Departments of Pediatrics and
Pathology, Stanford University, Stanford, CA 94305
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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. When both IL-4 and IL-5 were neutralized in this system,
AHR was still induced, suggesting that influenza-induced cytokines such
as IL-13, or mechanisms unrelated to cytokines, might be responsible
for the development of AHR. The length of time between influenza A
infection and i.n. exposure to OVA was crucial, because mice exposed to
i.n. OVA 15–30 days after viral inoculation developed neither AHR nor
OVA-specific tolerance. These mice instead acquired Th1-biased
OVA-specific immune responses associated with vigorous OVA-induced T
cell proliferation, and reduced production of OVA-specific IgE. The
protective effect of influenza A on AHR was dependent on IFN-,
because protection was abrogated with a neutralizing anti-IFN-
mAb. These results suggest that viral respiratory infection interferes
with the development of respiratory allergen-induced tolerance, and
that the time interval between viral infection and allergen exposure is
critical in determining whether viral infection will enhance, or
protect against, the development of respiratory allergen sensitization
and AHR. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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(1, 2). Both allergic and nonallergic individuals are exposed to
environmental aeroallergens, but only allergic individuals develop
allergen-specific Th2-biased immune responses to these allergens.
Nonallergic individuals remain tolerant to allergen exposure because
they lack allergen-specific IgE, lack functional immune reactivity to
these allergens, or develop protective allergen-specific Th1-biased
responses. The development of asthma is linked not only to respiratory allergen sensitization, but also to viral respiratory tract infections in early childhood. It is well known that asthma symptoms such as wheezing worsen after respiratory viral infection (3, 4). Furthermore, viral infection, for example with respiratory syncytial virus, during the first years of life greatly enhances the risk of developing asthma in children (5, 6), and experimental data in murine systems support this idea (7). Moreover, viral infection and respiratory allergies together appear to be synergistic as risk factors in producing symptoms of wheezing (8). These studies suggest that specific interactions between respiratory allergies and viral infections exist, where viral illnesses in early childhood may enhance the development of allergen sensitization. However, this relationship remains controversial, because many other epidemiological studies suggest that viral and bacterial infections, in fact, protect against the development of asthma and allergy (9, 10, 11, 12).
The purpose of this study was to determine the effects of infection
with influenza A virus on the development of respiratory allergen
sensitization and AHR in a murine model of asthma. We and others have
demonstrated that respiratory exposure to a prototypic allergen, OVA
(3), in naive mice leads to OVA-specific
CD4+ T cell unresponsiveness and lack of IgE
responsiveness, due primarily to deletion and functional inactivation
of Ag-specific CD4+ T cells
(13, 14, 15). Moreover, we recently demonstrated that such
respiratory Ag-induced tolerance prevented the development of AHR and
inflammation (16). Using this model system, we now report
that concurrent influenza A virus infection and intranasal (i.n.)
exposure to OVA abrogated the induction of OVA-induced tolerance,
promoted the expansion of functionally active allergen-specific Th
cells, enhanced the production of allergen-specific IgE, IL-4, IL-5,
IL-13, and IFN-, and prompted the development of AHR. When both IL-4
and IL-5 were neutralized in this system, AHR was still induced,
suggesting that influenza-induced cytokines such as IL-13 were
responsible for the development of AHR.
The length of time between influenza A virus infection and i.n.
exposure to OVA was crucial, because respiratory exposure to allergen
15–30 days after viral infection, during recovery phase from the
infection, abrogated tolerance induction but promoted a Th1-biased
response. Moreover, this response was associated with reduced
allergen-specific IgE production and normal airway reactivity. The
protective effect of influenza A on AHR was dependent on IFN-,
because it was abrogated with a neutralizing anti-IFN- mAb. Thus
influenza A virus infection abolishes respiratory allergen-induced
tolerance, but may enhance or protect against allergen-induced AHR
depending on the timing of respiratory allergen exposure. These results
strongly imply that respiratory viral infections in humans interrupt
the normal tolerance-inducing mechanisms that protect against the
development of allergic asthma, but may enhance subsequent protective
Th1-biased responses. Therefore, these results may explain the
conflicting results of clinical studies in humans demonstrating that
respiratory viral infections either enhance the risk of, or prevent the
development of, asthma.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Five- to 6-wk-old BALB/c or BALB/c IL-4-/- mice were purchased from The Jackson Laboratory (Bar Harbor, ME) and were housed in pathogen-free conditions at the laboratory animal facilities of Stanford University (Stanford, CA), in accordance with the guidelines of National Institute of Health. Mice used for experiments were sex and age matched.
Influenza A infection
Mice were anesthetized with methoxuflurane and inoculated i.n. with influenza A virus (attenuated strain HK-31 (H3N2)) in 40 µl PBS (diluted 1:5 v/v), generously provided by Dr. Peter Doherty (University of Tennessee, TN). The dose of virus used (240 hemagglutination U) causes severe, but nonlethal, pneumonia with complete viral clearance by day 10 after inoculation (17, 18). Control mice were treated with i.n. allantoic fluid (a.f.; also provided by Dr. Peter Doherty) diluted 1:5 in PBS.
Experimental protocols
Three, 15, or 30 days after infection, mice were lightly
anesthetized and received 100 µg grade V OVA in 30 µl of PBS
(Sigma, St. Louis, MO) i.n. on 3 consecutive days. Control mice
received an equivalent volume of PBS i.n. Ten days after the last
administration of i.n. OVA, the mice were immunized with 50 µg OVA in
2 mg aluminum hydroxide (alum) i.p. The mice were rechallenged 10 days
later with 50 µg i.n. OVA three times (Fig. 1
). In some experiments BALB/c mice
received 2 mg anti-IFN- mAb i.p. (XMG1.2; generous gift of Dr.
R. Coffman, DNAX Research Institute, Palo Alto, CA) 24 h before,
and at the time of viral inoculation, as well as before the
administration of i.n. OVA or PBS. In other experiments, BALB/c
IL-4-/- mice were used and were treated with
anti-IL-5 mAb (TRFK-5, 2 mg/dose i.p.; kind gift of Dr. R. Coffman,
DNAX Research Institute) 24 h before administration of i.n. OVA or
PBS. Control IL-4-/- mice received an isotype
control Ab (4G10, 2 mg/dose; kindly provided by Dr. S. Levy, Stanford
University).
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Airway responsiveness was assessed by methacholine-induced airflow obstruction from conscious mice placed in a whole body plethysmograph (model PLY 3211; Buxco Electronics, Troy, NY). Pulmonary airflow obstruction was measured by Penh using the following formula: Penh = (Te/RT-1) x (PEF/PIF), where Penh = enhanced pause (dimensionless), Te = expiratory time, RT = relaxation time, PEF = peak expiratory flow (ml/s), and PIF = peak inspiratory flow (ml/s), measured with a transducer (model TRD5100) and analyzed by Buxco system XA software (model SFT 1810). Measurements of methacholine responsiveness were obtained by monitoring Penh immediately after exposing mice for 2 min to nebulized 0.9% NaCl and of incremental doses of nebulized methacholine. Results were expressed for each methacholine concentration as the percentage of baseline Penh values after 0.9% NaCl exposure (19).
Analysis of airway inflammation
Following the sacrifice of mice, the trachea was cannulated, and the lungs were lavaged with 0.3 ml PBS (0.1% BSA, 0.5 mM EDTA) four times. The fluid was pooled, total cell numbers in the bronchoalveolar lavage (BAL) fluid were counted, and cytospin slides were prepared. The slides were stained with Diff-Quik (Dade Behring, Newark, DE) and cell differentials of at least 300 cells/slide were determined by light microscopy based on conventional morphologic criteria. In some animals, the lungs were removed, fixed in 10% formalin, routinely processed, and embedded in paraffin wax. Five-micrometer sections were prepared and stained with hematoxylin and eosin.
In vitro proliferation and cytokine assays
Lymph node cells were harvested, passed through a nylon mesh,
and cultured (5 x 105 cells/well) with or
without OVA in 0.2 ml DMEM (Sigma) supplemented with 10% FCS (Gemini
Bioproducts, Calabasas, CA), 2 mM L-glutamine, 20 µg/ml
gentamicin, and 5 x 10-5 M 2-ME. After
72 h, the cultures were pulsed with 1 µCi
[3H]thymidine for 12–16 h and the incorporated
radioactivity was measured in a Betaplate scintillation counter
(MicroBeta Trilux; Wallac, Gaithersburg, MD). To determine the
secretion of cytokines in the cultures, supernatants were collected at
day 4, and analyzed for levels of IL-4, IL-5, IL-13, and IFN- by
ELISA.
Measurement of OVA-specific Igs
Mice were bled at the time of sacrifice and OVA-specific Abs were measured using OVA-specific ELISA. For the measurement of OVA-specific IgG1 and IgG2a, plates were coated overnight with 5 µg/ml OVA. After washing and blocking, serial dilutions of sera were added for 24 h. Subsequently the plates were incubated with HRP-conjugated goat anti-IgG subclass-specific Abs (Southern Biotechnology Associates, Birmingham, AL), washed, and developed by adding o-phenylenediamine substrate. The OD was determined at 492 nm. Anti-OVA IgG1 and IgG2a mAbs 6C1 and 3A11, respectively, were used as standards for quantification of each IgG subclass (20), and measurements were performed within the linear range of the standard curves. For the determination of OVA-specific IgE, 5 µg/ml rat anti-mouse IgE mAb EM95 (generously provided by Dr. Robert Coffman, DNAX Research Institute, and Dr. Z. Eshhar, Weizman Institute, Rhovot, Israel) was used to coat the plates. After the samples were applied for 24 h, 10 µg/ml biotinylated OVA was added for 2 h followed by a 1-h incubation with HRP-conjugated streptavidin (Southern Biotechnology Associates). Plates were developed with o-phenylenediamine substrate and the OD was determined at 492 nm. Sera from mice hyperimmunized with OVA in alum was used as standard for the OVA-specific IgE ELISA, and was first standardized for IgE levels against an anti-OVA IgE mAb generously provided by E. Gelfand (National Jewish Center for Immunology and Respiratory Medicine, Denver, CO; Ref. 21).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We previously showed that i.n. administration of OVA induced
peripheral CD4+ T cell tolerance, characterized
by inability of the specific CD4+ T cells to
expand and produce cytokines after immunogenic restimulation
(14). The induction of i.n. tolerance effectively prevents
the development of AHR and inflammation upon further contact with the
allergen (16). To examine the effects of influenza A viral
infection on these processes, we infected BALB/c mice with influenza A
virus and administered OVA i.n. 3 days later (Fig. 1
A). Ten
days after exposure to i.n. OVA, the mice were treated with a protocol
to induce AHR by immunization with OVA with alum i.p. and subsequent
rechallenge with i.n. OVA. As expected, cells taken from bronchial
lymph nodes of control mice previously exposed to a.f. followed by i.n.
OVA (a.f./OVA) before i.p immunization with OVA, failed to proliferate
when stimulated in vitro with OVA (Fig. 2). However, cells from mice infected
with influenza before i.n. OVA exposure (Flu/OVA), proliferated
vigorously, indicating that infection with the virus abrogated the
induction of OVA-specific T cell unresponsiveness.
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(Fig. 3),
and did not secrete TGF-ß or IL-10 (data not shown). In contrast, T
cells from control mice treated only with our standard sensitization
protocol to induce AHR (a.f./saline) produced high levels of IL-4,
IL-5, and IL-13. Infection with influenza A before i.n. OVA exposure
(Flu/OVA) markedly increased secretion of IL-4, IL-5, and IL-13 and
particularly enhanced production of IFN- (Fig. 3). The levels of
IL-10 and TNF-
measured in the culture supernatants were very low,
while TGF-ß production was not detected in any of the cultures
performed (data not shown).
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; Ref. 13, 14, 15).
However, influenza virus infection with concurrent exposure to i.n. OVA
(Flu/OVA) resulted in secretion of high levels of OVA-specific IgE,
equivalent to IgE levels observed in the fully sensitized control group
(a.f./saline). These mice (Flu/OVA) also developed an increase in the
levels of the OVA-specific IgG2a (Fig. 3) and IgG1 (data not shown),
consistent with the induction by influenza A of an unrestricted T cell
cytokine profile. These observations indicated that infection with
influenza A virus abrogated the induction of i.n. tolerance, and
allowed the development of allergic sensitization with the development
of effector T cells with a mixed cytokine profile. Concomitant exposure to i.n OVA and influenza A infection results in the development of AHR
Infection with influenza A virus not only interfered with i.n.
tolerance induction, but also abrogated the protective effects of
tolerance on the development of AHR. Thus, Fig. 4A shows that influenza A
infection 3 days before exposure to i.n. OVA (Flu/OVA) resulted in a
significant degree of AHR, similar to that observed in the fully
sensitized control mice treated to induce AHR (a.f./saline). On the
contrary, mice tolerized by the administration of i.n. OVA (a.f./OVA)
before sensitization and challenge with OVA developed negligible AHR,
as we have previously shown.
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B). As expected, control mice infected with influenza A,
not exposed to the initial dose of i.n. OVA, but treated with the
protocol to induce AHR developed a high degree of AHR, with significant
airway eosinophilia (data not shown).
The degree of AHR and eosinophilia in the lungs of these mice also
reflected the histology in the lungs of mice taken 1 day after the last
administration of i.n. OVA. In control sensitized mice (a.f./saline),
the bronchiolar airways were filled with mucus and were surrounded by
an intense inflammatory infiltrate (Fig. 5A). In contrast, the
tolerized mice, exposed to i.n. OVA (a.f./OVA) before immunization to
induce AHR, had remarkably little evidence of inflammatory changes
(Fig. 5B) and were protected from AHR. However, abrogation
of i.n. tolerance and loss of protection against AHR due to influenza
virus infection correlated with significant inflammatory histopathology
in the lungs. In these mice (Flu/OVA), the high level of AHR correlated
with dense peribronchiolar, perivascular, and interstitial
inflammation, consisting mainly of lymphocytes, mononuclear cells, and
eosinophils (Fig. 5C). Furthermore, many of the bronchiolar
airways were filled with mucus and contained disrupted epithelium.
Thus, influenza A virus infection abrogated the induction of i.n.
tolerance, which resulted in exacerbation of allergen-induced
respiratory inflammation.
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Because influenza A virus infection induced the production of a
broad spectrum of cytokines, including IL-4 and IL-5, which are
important in the induction of AHR (22, 23, 24), we asked
whether the exacerbation of AHR and inflammation by influenza A in our
system was dependent on these two cytokines. For this purpose,
IL-4-/- BALB/c mice were infected with
influenza A virus and exposed to i.n. OVA before immunization with our
protocol to induce AHR. To eliminate the influence of IL-5 on the
development of the inflammatory response, the mice were also treated
with a neutralizing anti-IL-5 mAb during the initial i.n.
treatment, as well as during the later i.n. challenges. Control
IL-4-/- and anti-IL-5 mAb-treated mice
developed significant AHR when immunized with our protocol to induce
AHR (Fig. 6A). This suggested
that the presence of IL-4 and IL-5 was not an absolute requirement for
the induction of AHR (25). Additionally, exposure of such
mice lacking active IL-4 and IL-5 to i.n. OVA in the absence of
infection (a.f./OVA), led to the inhibition of AHR (Fig. 6A). In this group, the reduction in AHR was associated with
a reduced T cell proliferative response (16), indicating
that the induction of i.n. tolerance was independent of the presence of
IL-4 or IL-5. In contrast, the IL-4-/-,
anti-IL-5 mAb-treated mice (as well as wild-type mice), when
exposed concurrently with i.n. OVA and influenza A virus (Flu/OVA),
developed significant AHR (Fig. 6A). This implied that the
induction of AHR by influenza virus was also independent of IL-4
and IL-5.
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B). Similarly, examination of their lung histology revealed
inflammatory infiltrates with almost no eosinophils and no mucus
production, while the pulmonary infiltrates present in wild-type
controls contained numerous eosinophils and significant mucus
production (data not shown). These observations indicated that IL-4 and
IL-5 regulated the recruitment of eosinophils and mucus production in
the lung, but suggested that cytokines other than IL-4 and IL-5 (e.g.,
IL-13) produced in response to infection with influenza A, or
mechanisms unrelated to cytokines, controlled the development
AHR. Exposure to i.n. OVA late after influenza A infection does not induce T cell tolerance, but protects against the development of AHR
We next determined whether exposure to i.n. OVA late after
influenza A virus infection affected the induction of tolerance. For
this purpose, mice received i.n. OVA 15 or 30 days after inoculation
with virus before treatment with our standard protocol to induce AHR
(Fig. 1, B and C). As expected, T cells from
control mice exposed to a.f. followed by i.n. OVA (a.f./OVA) before i.p
immunization with OVA failed to proliferate when restimulated in vitro
(Fig. 7). However, T cells from mice
infected with influenza A then given i.n. OVA 15 days (Fig. 7) as well
as 30 days (data not shown) later (Flu/OVA) proliferated as vigorously
in vitro in response to OVA as did T cells from control sensitized mice
(a.f./saline), indicating that the induction of i.n. tolerance was
still abrogated by infection with influenza A.
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). In addition, the down-regulation in
Th2 cytokine secretion was associated with enhanced IFN- production.
Moreover, OVA-specific IgE in serum from these mice was significantly
reduced compared with control sensitized mice, with a more significant
decrease observed in mice that received OVA 30 days after viral
infection (Fig. 8). Additionally, serum OVA-specific IgG2a levels in
the infected mice (Flu/OVA) exceeded those of the control sensitized
(a.f./saline) and tolerized groups (a.f./OVA; Fig. 8).
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A; day 30, data not shown).
Additionally, the number of eosinophils observed in BAL fluid in these
mice was reduced, particularly in mice that received i.n. OVA 30 days
after viral infection (Fig. 9B). Similarly, a reduction in
the inflammatory infiltrate was observed in the lungs of these mice
(Fig. 5D). These results taken together indicate that
influenza A alters the pulmonary environment, disrupting its capacity
to induce T cell unresponsiveness, and later shifting immune
responsiveness toward a Th1 pattern, which protects against the
development of AHR.
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We examined the mechanism by which exposure to i.n. OVA late after
influenza A infection protected the mice from the development of AHR.
To this end, mice were treated with a neutralizing anti-IFN- mAb
during viral infection, as well as during all exposures to i.n. OVA.
Fig. 10A shows that absence
of active IFN- in influenza A-infected mice exposed to i.n. OVA 15
or 30 days later (Flu/OVA/anti-IFN-) reversed the protective
effects of the virus on AHR. The increase in airways reactivity in
these mice was associated with a notable increase in airway
eosinophilia (Fig. 10B). Thus, protection from AHR in this
system was very much dependent on the presence of IFN-, produced as
a consequence of influenza A virus infection.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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. However, respiratory exposure to allergen late
after influenza A infection, during the recovery period from infection,
disrupted tolerance induction, but promoted an IFN--predominant
response which was associated with protection from the development of
AHR. Thus, the respiratory effects of influenza A infection depended on
the phase of infection during which the primary exposure to OVA took
place. In healthy, nonallergic individuals, mechanisms exist that limit immune responses to nonreplicating, environmental Ags encountered at the respiratory mucosal surface. The respiratory mucosa is continuously exposed to a wide variety of environmental Ags, and indiscriminate immunological responses to innocuous Ags could be detrimental, and cause tissue injury that interferes with respiratory gas exchange. We and others have demonstrated that exposure of the respiratory mucosa to nonreplicating Ags in the absence of inflammatory signals, results in peripheral immunological tolerance, characterized by a reduced T cell proliferative response upon subsequent encounter with the same Ag (13, 14, 26). Exposure to respiratory Ag transiently activates Ag-specific CD4+ T cells, but this is followed by a degree of T cell deletion and by functional inactivation of any remaining Ag-specific CD4+ T cells (14, 26). Moreover, the induction of allergen-specific tolerance by respiratory exposure to allergen prevents subsequent production of allergen-specific IgE and prevents the development of allergen-induced AHR (16), strongly suggesting that immunological tolerance induced by respiratory exposure to allergen protects against the development of allergic disease and asthma.
The functional outcome of primary contact with aeroallergen is of
critical significance for the regulation of allergic reactivity,
because the initial contact with allergen can generate either tolerance
or immune responsiveness. Infection with influenza A generates an
inflammatory process in the lung parenchyma and associated lymphoid
tissues that is characterized early on by increased levels of both Th1
and Th2 cytokines (18, 27) and by the activation and
maturation of dendritic cells (28). Exposure of the
respiratory mucosa to OVA under these circumstances did not result in
tolerance induction, but rather facilitated allergen sensitization,
enhanced the production of OVA-specific IgG2a and IgE, and the
expansion of OVA-specific CD4 T cells secreting high amounts of IL-4,
IL-5, IL-13, and IFN-. Moreover, mice infected with influenza A and
concurrently exposed to i.n. OVA developed significant AHR and
eosinophilic inflammation. These results demonstrated that influenza
virus infection disrupted allergen-induced tolerance and allowed OVA
sensitization resulting in the development of AHR.
In our system, neutralization of IL-4 and IL-5 in mice exposed to i.n. OVA early after infection with influenza A virus (by treating IL-4 knockout mice with anti-IL-5 mAb) did not abrogate the induction of AHR. Nevertheless, the absence of IL-4 and IL-5 was associated with greatly reduced lung eosinophilia, confirming the important role of these two cytokines in the recruitment of eosinophils in the airways, but not in the development of AHR (25, 29). The observed AHR in these mice correlated with the presence of IL-13, suggesting that the induction of IL-13 by influenza A infection might be responsible for the development of AHR. IL-13 has been shown recently to play a primary role in the induction of AHR in murine models of asthma (30, 31), and was produced by bronchial lymph node T cells when our mice were exposed to OVA 3 days but not 30 days after influenza A infection. Alternatively, other cytokines, for example IL-9, or other nonimmunological mechanisms related to the cytopathic effect of the virus on respiratory epithelium and smooth muscle might be responsible for the elevated bronchial reactivity (6, 25, 29). In addition, virus-induced CD8+ T cells producing Th2 cytokines might aggravate the development of AHR (32, 33, 34).
The AHR induced in infected mice exposed to i.n. OVA 3 days after viral
inoculation could not be reversed by the Th1-like mediators, such as
IFN-, which were also co-produced during the influenza A virus
infection. These Th1-like factors, including cytolytic CD8 cells, are
prominent in virus-infected mice, are required for eliminating
influenza A virus (35), and might direct the
differentiation of bystander responses toward a Th1 predominance.
However, it appears that the presence of high levels of Th2 cytokines
at the initial stage of infection dominated over the effects of the Th1
cytokines (36), resulting in an allergic inflammatory
response and AHR. Alternatively, it is possible that when both Th1 and
Th2 cytokines are present in large quantities, they are synergistic or
codominant in producing inflammatory responses (19, 37, 38). This is consistent with observations demonstrating that Th1
cells participate concomitantly with Th2 cells in the airways of
asthmatic individuals, and appear to enhance the development of
allergic inflammation (19, 39, 40).
Although influenza virus is completely cleared from the lungs within
7–10 days after the initiation of infection (17), the
inflammatory effects of influenza A virus in the lung persisted for
several weeks after the initiation of infection. Although early
exposure to i.n. OVA enhanced the development of AHR, exposure of mice
to i.n. OVA late after influenza A infection protected against AHR.
Thus, mice exposed to i.n. OVA 30 days after influenza A infection were
not tolerized, but developed an IFN--dominant OVA-specific immune
response, accompanied by reduced airway inflammation and reactivity,
and with production of little or no IL-4, IL-5, or IL-13. In these
mice, a degree of airway inflammation was present, characterized by the
accumulation of monocytes, lymphocytes, neutrophils, and some
eosinophils. The protective effect of influenza A virus on AHR was
dependent on IFN-, because it was reversed by the administration of
a neutralizing anti-IFN- mAb. These results indicate that
influenza virus infection can direct bystander responses toward the Th1
pathway, abrogating respiratory allergen-induced tolerance, and
producing allergen-specific immune responses that protect against the
development of AHR, but only at a time point late after infection.
Although potent allergen-specific Th1 responses in the lung produce an
inflammatory process that can result in parenchymal tissue damage
(19), the effects of the IFN--dominant profile observed
in these mice may have been mitigated by the simultaneous local
production of inhibitory or protective cytokines such as IL-10
(41, 42).
In summary, our results clearly indicate that respiratory infection with influenza A alters the pulmonary environment and disrupts its capacity to induce allergen-specific T cell unresponsiveness. The interruption of respiratory-induced tolerance resulted in the generation of functional allergen-specific Th cell immunity, the features of which depended on the stage of infection when primary respiratory contact with the allergen occurred. Concurrent exposure to allergen produced a pathological Th2-dominant response, associated with the development of AHR, whereas late exposure to allergen resulted in Th1 predominance that protected against the development of AHR. These results demonstrate that respiratory viral infection may provide either protective or deleterious effects with regard to allergen-sensitization and the development of AHR.
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Acknowledgments |
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Footnotes |
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2 D.T.U. and D.B.L. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Dale T. Umetsu, Division of Immunology and Transplantation Biology, Department of Pediatrics (Room G309), Stanford University, Stanford, CA 94305-5208.
4 Abbreviations used in this paper: AHR, airway hyperreactivity; a.f., allantoic fluid: BAL, bronchoalveolar lavage; i.n., intranasal, intranasally.
Received for publication January 28, 2000. Accepted for publication July 5, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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+ T cells or interferon (IFN)- in a murine model of allergen sensitization. J. Exp. Med. 187:721.-interferon mRNA in vivo and maintain high levels of mRNA expression for interleukin-5 (IL-5) and IL-10. J. Virol. 68:7575. and interferon- by bronchoalveolar leukocytes from patients with bronchial asthma. Am. Rev. Respir. Dis. 147:291.[Medline]
and interleukin-10. J. Exp. Med. 183:2559.This article has been cited by other articles:
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C.-K. Yu and C.-L. Chen Activation of Mast Cells Is Essential for Development of House Dust Mite Dermatophagoides farinae-Induced Allergic Airway Inflammation in Mice J. Immunol., October 1, 2003; 171(7): 3808 - 3815. [Abstract] [Full Text] [PDF]
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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]
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 E. Hak, A. W. Hoes, D. E. Grobbee, J. W. J. Lammers, G. A. van Essen, A. M. van Loon, and T. J. M. Verheij Conventional Influenza Vaccination Is Not Associated with Complications in Working-Age Patients with Asthma or Chronic Obstructive Pulmonary Disease Am. J. Epidemiol., April 15, 2003; 157(8): 692 - 700. [Abstract] [Full Text] [PDF]
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 R. F. Lemanske Jr. Is Asthma an Infectious Disease?: Thomas A. Neff Lecture Chest, March 1, 2003; 123 (2009): 385S - 390S. [Abstract] [Full Text] [PDF]
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C.-L. Chen, C.-T. Lee, Y.-C. Liu, J.-Y. Wang, H.-Y. Lei, and C.-K. Yu House Dust Mite Dermatophagoides farinae Augments Proinflammatory Mediator Productions and Accessory Function of Alveolar Macrophages: Implications for Allergic Sensitization and Inflammation J. Immunol., January 1, 2003; 170(1): 528 - 536. [Abstract] [Full Text] [PDF]
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 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]
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D. M. Walter, J. J. McIntire, G. Berry, A. N. J. McKenzie, D. D. Donaldson, R. H. DeKruyff, and D. T. Umetsu Critical Role for IL-13 in the Development of Allergen-Induced Airway Hyperreactivity J. Immunol., October 15, 2001; 167(8): 4668 - 4675. [Abstract] [Full Text] [PDF]
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S. D. Hurst, B. W. P. Seymour, T. Muchamuel, V. P. Kurup, and R. L. Coffman Modulation of Inhaled Antigen-Induced IgE Tolerance by Ongoing Th2 Responses in the Lung J. Immunol., April 15, 2001; 166(8): 4922 - 4930. [Abstract] [Full Text] [PDF]
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