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Department of Environmental Health Sciences, School of Hygiene and Public Health, Johns Hopkins University, Baltimore, MD 21205;
College of Medicine, University of Cincinnati, Cincinnati, OH 45267;
Uniformed Services University of Health Sciences, Bethesda, MD 20814
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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message or protein levels. In contrast,
treatment with anti-B7-1 mAbs had no effect on allergen-induced
airway hyperresponsiveness, IgE production, or cytokine production,
however, it significantly suppressed pulmonary eosinophilia. We
conclude that B7-2 provides the necessary costimulatory signal required
for the development of in vivo allergic responses to inhaled allergen
exposure. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We have recently provided additional support for this hypothesis in a murine model of Ag-induced airway hyperresponsiveness and pulmonary eosinophilia in which allergic responses are CD4+ T cell dependent (8) and associated with increases in Th2 cytokines in the lung (9). In addition, we demonstrated that administration of rIL-12, a cytokine important in Th1 cell differentiation, both prevented and reversed the development of allergic airway responses in mice (9). Despite considerable evidence suggesting that T lymphocytes play a pivotal role in the pathogenesis of asthma, the molecular signals that direct the differentiation of naive T cells into pathogenic Th2 cytokine-producing cells in the lung in response to inhaled allergens are not well understood.
CD4+ T cell activation requires two distinct signals from APC (10). The first signal, which confers specificity, is provided by the interaction of the TCR with MHC II complexes on APC. A second costimulatory signal can be provided by APC-borne ligands for the CD28 and CTLA-4 receptors on T cells. TCR ligation in the absence of costimulation induces Ag-specific T cell anergy (11). The ligands for CD28 and CTLA-4 are B7-1 (CD80) and B7-2 (CD86) (12, 13). Blockade of the B7/CD28 pathway with CTLA4Ig, a soluble fusion protein (14), has been shown to effectively inhibit T cell activation in vitro (15, 16) and in vivo (17, 18, 19, 20, 21, 22). Recently, some studies have suggested that B7/CD28-CTLA-4 interactions may not only be important in T cell activation and IL-2 production, but may also play a role in T cell differentiation with B7-1 favoring development of Th1 cells and B7-2 favoring Th2 cells (22, 23, 24). In contrast, other studies have suggested that B7-1 and B7-2 molecules can substitute for each other during Th2 differentiation (25, 26). Few studies have examined the potential role of these costimulatory molecules in the development of T cell-dependent allergic airway responses.
In the present study, we examined the relative contribution of B7-1 and B7-2 to the development of Th2-mediated allergic airway responses in an in vivo murine model of asthma, which we have previously described (8, 9). Our results demonstrate that B7-2 costimulatory molecules are required for the development of a type 2 cytokine pattern as well as the development of allergic airway responses. In contrast, treatment with anti-B7-1 did not block the course of the type 2 immune response.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Six-week-old male A/J mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and were housed in a laminar flow hood in a virus-free animal facility for the duration of the experiments. The studies reported here conformed to the principles for laboratory animal research outlined by the Animal Welfare Act and the Department of Health, Education and Welfare (National Institutes of Health) guidelines for the experimental use of animals (n = 6–8 mice/experimental group).
Special reagents
Abs used for the in vivo cytokine intervention experiments included rat anti-mouse B7-2 (GL1) (27), hamster anti-mouse B7-1 (16-10A1) (28), control isotype-matched rat IgG2a (GL117), and control normal hamster IgG, which were prepared as previously described (29).
Effects of B7 blockade on allergic airway responses to Ag challenge
Mice were sensitized by i.p. injection of OVA (10 µg in 0.3 ml PBS) or PBS alone (controls). Two weeks later, mice were anesthetized with a mixture of ketamine and xylazine (45 and 8 mg/kg, respectively) and challenged by aspiration. Specifically, mice are placed on a board in a supine position. The animal’s tongue extended with lined forceps and 50 µl of a 1.5% solution of OVA or an equivalent volume of PBS (control) is placed on the back of the tongue. We have examined the deposition pattern of the Ag delivered in this manner by using Evans blue dye. We find that a small amount of the Ag is deposited in the trachea and the remainder is deposited in the airways. No Ag is detected in the esophagus or stomach.
OVA-treated (both sensitized and challenged with OVA) and PBS-treated mice (both sensitized and challenged with PBS vehicle) were injected i.v. with anti-B7-1 (100 µg), anti-B7-2 (100 µg), or a combination of both anti-B7-1 and anti-B7-2 mAbs (total of 200 µg) 24 h prior to OVA or PBS challenge. Control animals were administered either 100 µg hamster IgG, 100 µg IgG2a (GL117), or 100 µg of both hamster IgG and IgG2a (GL117). On the day of the challenge, Abs (100 µg/mouse) were administered with the PBS or OVA by aspiration in a total volume of 50 µl. Ninety-six hours after challenge, airway responsiveness to i.v. acetylcholine challenge was determined, the number of inflammatory cells in BAL fluids was determined, lungs were saved for measurement of cytokine mRNA levels, and blood was taken for analysis of Ig levels.
Airway responsiveness measurements
Airway responsiveness to i.v. acetylcholine challenge was measured as previously described with minor modifications (8, 9). Briefly, mice were anesthetized with sodium pentobarbital (17.5 mg/ml), intubated with a 20-gauge tracheal cannula, and ventilated at a rate of 120 breaths/min with a constant tidal volume of air (0.2 ml). Airway pressure was measured with a pressure transducer via a port of the tracheal cannula. Muscle paralysis was provided by i.v. administration of decamethonium bromide (25 mg/kg). After establishment of a stable airway-pressure recording, acetylcholine was injected i.v. (50 µg/kg) and the changes in airway pressure were recorded. Airway responsiveness was defined by the time-integrated change in peak airway pressure (airway pressure-time index; cm H2O per s).
Assessment of airway inflammation
After airway responsiveness measurements, lungs were lavaged thoroughly with 1 ml of HBSS solution without calcium or magnesium plus 10% FBS. The lavage fluid was centrifuged (300 x g x 10 min), the supernatant was removed for cytokine analysis, and the cell pellet was resuspended in 1 ml of HBSS solution plus 10% FBS, and counted with a hemocytometer. Slide preparations were stained with Diff-Quick (Baxter, McGaw Park, IL) and BAL cell differential percentages were determined based on light microscope evaluation of >500 cells/slide.
Quantitation of cytokine mRNA levels in the lung
RNase-free plastic and water were used throughout the assay. Tissues were homogenized in RNAzol B (Cinna/Biotecs, Friendswood, TX) at 50 mg of tissue/ml. Purified RNA (10 µg) was subjected to electrophoresis on a 2% formaldehyde gel containing ethidium bromide (30). The gel was photographed and individual lanes were examined for the presence of 18S and 28S ribosomal bands, the absence of RNA degradation, and the quantity of RNA loaded onto each lane.
The procedures for reverse transcription and PCR were previously reported (30) and are briefly described here. RNA samples were reverse transcribed with Superscript RT (Bethesda Research Laboratories, Rockville, MD), and cytokine-specific primers were used to amplify selected cytokines (30). For each cytokine, the optimum number of cycles (i.e., the number of cycles that would produce a detectable quantity of cytokine product DNA that was directly proportional to the quantity of input mRNA) was determined experimentally. To verify that equal amounts of undegraded RNA were added in each RT-PCR reaction within an experiment, the "housekeeping gene," hypoxanthine guanine phosphoribosyltransferase (HPRT), was used as an endogenous internal standard, and amplified with specific primers at the number of cycles at which a linear relationship between input RNA and final HPRT product was detected. Although HPRT values did not usually vary more than two- to threefold, values for specific cytokines were normalized to HPRT values. Amplified PCR product was detected by Southern blot analysis and the resultant signal was quantitated with a PhosphorImager (Molecular Dynamics, Sunnyvale, CA). Mean values are expressed relative to the means of the PBS-challenged animals, which were arbitrarily given a value of 1.
Quantitation of cytokine protein levels in BAL fluid
After airway measurements, mice were lavaged thoroughly with 1
ml of HBSS solution without calcium and magnesium plus 10% FBS. The
lavage fluid was centrifuged, and aliquots of the supernatants were
stored without further treatment at -80°C until analyzed by ELISA.
ELISAs for IL-4, IL-5, and IFN- were conducted using matching Ab
pairs obtained from PharMingen (San Diego, CA), according to the
manufacturer’s instructions. The following Ab pairs were used for
ELISA detection of IL-4, IL-5, and IFN-, respectively: BVD4-1D11 and
BVD6-24G2; TRFK5 and JES1-39D10; R46A2 and XMG1.2. OD readings of
samples were converted to picograms per milliliter using values
obtained from standard curves generated with varying concentrations of
recombinant IL-4, IL-5 and IFN- (2000 pg/ml-5 pg/ml). The limit of
detection was 5 pg/ml for each assay.
OVA-specific IgG1 and IgG2a ELISA assays
Sera were obtained from blood taken during exsanguination of the
animals after airway measurements. IgG subclass specific ELISAs were
used to quantitate OVA-specific IgG1 and IgG2a Ab levels in serum.
Briefly, 96-well Corning ELISA plates were coated with 50 µl of OVA
(100 µg/ml) in HBSS overnight at room temperature. Sixteen hours
later, wells were blocked with the addition of PBS-10% FBS (200
µl/well) for 2 h at room temperature. Following blocking, the
plates were washed with PBS-Tween-20, sera were added (100 µl/well of
a 1:100 dilution in PBS-1% FBS), and plates were incubated overnight
at 4°C. Plates were then washed with PBS-Tween and incubated with
biotin-conjugated anti-mouse IgG1 (1:2000; 1 chain
specific) or anti-mouse IgG2a (1:2000; 2a chain
specific; PharMingen) for 1 h at room temperature. After washing,
plates were blotted dry and developed with 100 µl of an avidin
peroxidase solution (ABTS, Kirkegaard and Perry, Gaithersburg, MD).
Plates were read at 405 nm.
Quantitation of total serum IgE
Sera were obtained from blood taken during exsanguination of the animals after airway measurements and 100 µl (1:50 dilution in 1% FBS in PBS) was added/well. An IgE-specific ELISA was used to quantitate total IgE Ab levels in serum using matching Ab pairs (R35-72 and R35-92) obtained from PharMingen according to the manufacturer’s instructions. OD 405 readings of the samples were converted to picograms per milliliter using values obtained from standard curves generated with varying concentrations of IgE and the final concentration was obtained by multiplying by the dilution factor.
Data analysis
Data are summarized as mean ± SE. The statistical analyses of the results were performed by analysis of variance using Fisher’s least significant difference test for multiple comparisons. Probability values <0.05 were considered significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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As B7-1 and B7-2 molecules are thought to be important in Th
cell differentiation, we sought to determine the relative contribution
of B7-2 and B7-1 to the development of Th2-mediated Ag-induced airway
hyperresponsiveness and inflammation. As previously reported (8, 9),
airway reactivity to i.v. acetylcholine challenge in OVA-treated mice
was significantly increased compared with that in PBS-treated mice
(Fig. 1
). Strikingly, anti-B7-2
treatment completely ablated airway hyperresponsiveness to
acetylcholine in OVA-treated mice as compared with airway responses of
OVA-treated mice receiving the isotype-matched Ab (GL117). In marked
contrast, anti-B7-1 mAb treatment had no significant effect on
airway reactivity in OVA-treated mice as compared with their controls
(OVA + hamster IgG). Isotype-matched control Ab (i.e., hamster IgG
or rat IgG2a (GL117)) administration had no significant effect on
airway reactivity in OVA-treated mice. Combining anti-B7-1 and
anti-B7-2 mAb treatments suppressed airway responses to the same
degree as anti-B7-2 mAb treatment alone. These results demonstrate
the importance of B7-2 molecules in the functional airway responses to
T cell activation by inhaled Ags.
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A).
Following OVA sensitization and challenge no significant increases in
BAL macrophages were observed, however, there were marked increases in
the number of BAL eosinophils (Fig. 2B). Anti-B7-2 treatment
of OVA-treated mice resulted in virtual ablation of eosinophils in the
BAL, while anti-B7-1 partially suppressed the number of eosinophils
recovered in the lavage fluid. The combination of anti-B7-1 and
B7-2 mAbs did not result in any additional significant inhibitory
effect on eosinophil numbers over that observed with anti-B7-2
treatment alone. All three isotype-matched control Abs had a tendency
to reduce alveolar macrophage numbers although not significantly;
however, they had no significant effect on eosinophil numbers in
the BAL.
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To determine the role of B7 molecules in T cell
differentiation and cytokine production, we examined the effects of
blockade of B7-1, B7-2, or both on IL-4, IL-5, and IFN- mRNA and
protein levels. Detectable mRNA and protein levels of IL-4, IL-5, and
IFN- were observed in PBS-treated mice (Figs. 3, 4, and
5). As we have previously demonstrated
(9), following Ag challenge significant increases in both mRNA and
protein levels of the type 2 cytokines, IL-4 and IL-5, were observed,
whereas no significant increases in the type 1 cytokine, IFN- were
found. Ag challenge also induced significant increases in IL-10 mRNA
levels as compared with PBS controls (Fig. 6). Anti-B7-2 or the combination of
anti-B7-1 and anti-B7-2 mAbs significantly suppressed
Ag-induced increases in protein levels of IL-4 and IL-5 as compared
with their respective isotype Ab controls, while having no effect on
IFN- levels. In marked contrast, anti-B7-1 did not significantly
alter IL-4, IL-5, or IFN- mRNA or protein levels in OVA-treated mice
as compared with hamster IgG treatment. Interestingly, the combination
of anti-B7-1 and anti-B7-2 Abs significantly increased BAL
IFN- protein levels in PBS-treated mice. Isotype control Ab
administration to OVA-treated mice had no significant effect on BAL
IL-4 and IL-5 protein levels as compared with OVA-treated mice
receiving no Ab treatments. These results demonstrate that B7-2
provides costimulation for the differentiation of T cells into type
2-producing cells in response to inhaled Ag, and suggests that B7-1
does not contribute to the immune response in this model, at least to
the extent that the dose of anti-B7-1 Ab used inhibited B7-1
interactions.
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To examine the role of B7 molecules in humoral responses to
inhaled OVA exposure, we measured OVA-specific levels of IgG1 and IgG2a
and total IgE in serum samples from animals receiving Abs to B7-1,
B7-2, or both. Administration of anti-B7-2 mAb to Ag-treated mice
resulted in significant suppression of OVA-specific IgG1 when compared
with mice treated with the isotype control Ab GL117, while having no
effect on IgG2a levels (Fig. 7). On the
other hand, anti-B7-1 did not affect either IgG1 or IgG2a levels.
Combined mAb treatment did not result in any significant inhibitory
effect on Ig levels over that observed with anti-B7-2 treatment
alone. Isotype-matched control mAb treatment had no effect on
OVA-specific serum levels of IgG1 or IgG2a.
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). Anti-B7-2 mAb treatment abolished
OVA-induced increases in IgE levels when compared with isotype control
Ab-treated mice, while anti-B7-1 had no effect. Isotype-matched
control Abs had no significant effect on IgE levels in either PBS- or
OVA-treated mice. As IgE Ab production is IL-4 dependent, these results
lend further support for the role of B7-2 costimulatory molecules in
type 2 cytokine production as well as in the development of allergic
responses.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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It has recently been demonstrated that T cell activation requires
multiple signals in addition to those conveyed through interaction of
the TCR with MHCII complexes on APC (10). One of the most well
characterized costimulatory signaling pathways involves the CD28 and
CTLA-4 molecules that are expressed on T cells and their ligands, B7
molecules that are expressed on APC (11, 12, 13). We have recently
demonstrated that CTLA4Ig, a fusion protein that inhibits the
interaction of B7 molecules with both CD28 and CTLA-4, ablated the
development of airway hyperresponsiveness, eosinophilic inflammation,
and elevations in serum IgG1 and IgE Abs when administered either prior
to sensitization or prior to local lung challenge (34).
Inhibition of these responses was associated with suppression of Th2
cytokines without any changes in the Th1 cytokine, IFN-. These
studies demonstrated that B7 molecule interaction with either CD28 or
CTLA-4 was important both in the initial sensitization step and in the
subsequent challenge response in the lung. Our findings support that of
previous studies using similar murine models (35, 36). To date at least
two members of the B7 family have been identified, namely B7-1 (CD80)
and B7-2 (CD86) (12, 13). Considerable controversy exists as to whether
these molecules are interchangeable or mediate distinct functions
through CD28 (22, 23, 24, 25, 26). Some studies have supported the concept that
they mediate distinct functions and moreover that B7-1 is important in
Th1 cell differentiation and that B7-2 molecules are important in Th2
cell differentiation (22, 23, 24). However, previous in vitro studies have
suggested that either B7-2 costimulation promotes the differentiation
of naive T cells toward a Th2 phenotype (24) or that B7-1 or B7-2
interactions with CD28 can support Th2 cell differentiation (25). The
present study was undertaken to determine whether the ligation of B7-1,
B7-2, or both molecules was required for development of a type 2
mucosal immune response to Ag exposure in a murine model.
Our results demonstrate that B7-2, but not B7-1, costimulation
is necessary for the development of allergic responses to
inhaled Ags in this murine model. Strikingly, B7-2 blockade
completely eliminated Ag-induced airway hyperresponsiveness,
eosinophilic inflammation, and elevations in serum IgE levels.
In conjunction with its inhibitory effects on these
functional responses, anti-B7-2 mAb ablated Ag-induced
increases in Th2 cytokines in BAL fluids, with no effect on IFN-
levels. As there were no significant increases in IFN- after Ag
challenge, it is not surprising that anti-B7-2 mAb treatment did
not affect IFN- levels. In contrast, anti-B7-1 blockade did not
result in suppression of Ag-induced airway hyperresponsiveness, IgE
production, or Th2 cytokine production. These results provide evidence
that B7-2 costimulation can play an essential role in the development
of allergic asthma.
Although B7-2 was required for the development of this type 2
allergic immune response, blocking B7-2 interactions did not cause
immune deviation toward increased IFN- expression, nor did blocking
B7-1 interactions promote a more severe allergic response. Similarly,
we have shown that CTLA4Ig treatment of OVA-sensitized and challenged
A/J mice suppressed Ag-induced Th2 cytokine production, but did not
alter IFN- levels (37). Our results are in contrast to those of
Tsuyuki et al. (35) who demonstrated using a similar Ag exposure model
with SV129 mice that anti-B7-2 mAb administration did in fact
induce increases in IFN- levels in in vitro-activated lung T cells.
These differences may reflect the inherent susceptibility of the A/J
strain to the development of Th2 responses and that IFN- production
or pathways associated with IFN- production are deficient in these
mice. Consistent with this is our finding that if these animals are
given exogenous IL-12 they will produce IFN-, which effectively
ablates the development of the allergic phenotype (9). Another
potential difference is that in our study cytokines were measured in
BAL fluids taken at the time of measurement of allergic airway
responses whereas in their study, IFN- levels were derived from
isolated lung cells stimulated in vitro with anti-CD3 Abs.
Our studies demonstrate that B7-2, but not B7-1, costimulation is
necessary for T cell help leading to B cell activation and secretion of
IgG1 and IgE. Since these Abs are associated with Th2 cell effector
function, they provide further evidence that B7-2 costimulation is
required for IL-4 production and the development of a type 2 immune
response (7). These observations are consistent with our previous
finding that CTLA4Ig prevents the development of humoral responses in
allergen-challenged A/J mice (34). Consistent with the lack of increase
in IFN- production in anti-B7-2-treated animals, IgG2a levels,
which are thought to be IFN- dependent, were not affected by
anti-B7-2 treatment. The lack of involvement of B7-1 in
OVA-induced Ab production was also demonstrated using Y100F-Ig, which
recognizes B7-1 not B7-2, in a murine model of Ag-induced airway
eosinophilia (37).
One interesting finding was that CTLA4Ig administration to mice before Ag sensitization resulted in blockade of OVA-specific Abs of all isotypes studied (IgE, IgG1, and IgG2a), whereas when it was administered prior to Ag challenge it suppressed only IgE and IgG1 with no effect on IgG2a levels. Administration of anti-B7-2 Abs reproduced the effect of CTLA4Ig on Ab production when it was given prior to local lung challenge. These results suggest that perhaps IgE and IgG1 Ab increases were due to Ag presentation in the lung following local Ag challenge and that a more mixed response occurs during systemic sensitization. This is consistent with our observation that IgG1 and IgE Ag production is markedly elevated following local Ag challenge as compared with that following systemic sensitization alone (M. Wills-Karp and A. M. Keane-Myers, unpublished observations). This hypothesis is supported by a recent report by Chvatchko et al. (38) in which they demonstrated the formation of germinal centers within the lung parenchyma, which predominantly produced OVA-specific IgG1 and IgE in mice challenged intratracheally with OVA.
Surprisingly, anti-B7-1 treatment of OVA-sensitized and challenged
animals partially suppressed OVA-induced increases in pulmonary
eosinophilia, but not to the extent that anti-B7-2 treatment alone
did. This finding is consistent with the reports of other investigators
using similar murine models of allergic airway responses (37). Harris
et al. demonstrate that blockade of B7-1 with a mutant form of CTLA4Ig,
which specifically blocks B7-1, significantly reduced Ag-induced tissue
eosinophilia, but had no effect on blood eosinophilia or IgE levels
(37). In contrast to the partial suppression of eosinophilia by
anti-B7-1 Abs, B7-2 blockade virtually ablated Ag-induced increases
in BAL eosinophils. This inhibition was concomitant with the
suppression of both IL-4 and IL-5 BAL levels. On the other hand,
blockade of B7-1 did not inhibit Ag-induced increases in either IL-4 or
IL-5 levels. This effect was also not mediated via increases in IFN-
as no increases in IFN- levels were observed following anti-B7-1
treatment of OVA-sensitized animals in our study. These results suggest
that the partial inhibitory effect of anti-B7-1 is due to non-IL-5
mediated processes, which contribute specifically to recruitment of
eosinophils into tissues such as the production of RANTES and/or
eotaxin (39, 40).
As blockade of B7-2 2 wk after the initial sensitization was effective at suppressing the development of this type 2 immune response, our results suggest that B7 costimulatory molecules are required for the activation of T cells during this secondary response. Previous in vitro (41) and in vivo (22, 42) studies have suggested that B7 costimulatory molecules may not be required for effector and memory T cell activation and cytokine production. Our results suggest that B7-2 molecules play a pivotal role in triggering of the Th2 challenge immune response in this murine model of allergy, suggesting that costimulatory signals may be important at these later stages of T cell differentiation. Consistent with this hypothesis, Finck et al. (19) has recently shown that CTLA4Ig administration can markedly ameliorate disease severity in a murine model of lupus, if administered subsequent to the development of disease. Although this effect may also be attributed to the inhibition of newly recruited T cells during this chronic disease, it is unlikely that this is the case in our allergy model, given the acute effect, within 96 h, of blocking B7-2 interactions.
Consistent with our findings, the importance of B7-2 in the differentiation of Th2 cells has also been recently demonstrated in an in vivo model of experimental allergic encephalomyelitis (23). In this model, Th1 cytokine-producing cells are associated with the disease phenotype. Anti-B7-1 treatment (resulting in Th2 cell expansion) ameliorated the disease, whereas anti-B7-2 exacerbated the disease, presumably resulting in the expansion of Th1 cells. In contrast, type 2 immune responses in response to infection with the nematode parasite, Heligmosomoides polygyrus, require both B7-1 and B7-2 costimulation, as blockade of both B7-1 and B7-2 was required to inhibit H. polygyrus-induced type 2 immune responses such as increases in serum IgG1 and IgE levels, the expansion of lymph node germinal centers, elevated blood eosinophils, and increased mucosal mast cells (43). These studies indicate that either B7-1 or B7-2 ligand interactions can provide the required costimulatory signals that lead to T cell effector function during a type 2 in vivo immune response. Thus it is clear that the requirements for costimulatory molecules during immune responses are quite complex and are likely to depend on a number of factors unique to each specific type of immune response.
The distinct requirements for B7-2 costimulation observed in this model are likely due to differential expression of B7-1 and B7-2, as other investigators have recently shown that both lung macrophages (37) and lung B cells (35) express predominantly B7-2 following inhalational exposure to OVA of mice of two different genetic backgrounds. One possible explanation for this differential expression of B7 molecules is that previous studies have indicated that there are clear differences in the kinetics of expression of B7-1 and B7-2 during an immune response (44, 45). B7-2 is constitutively expressed on monocytes and rapidly up-regulated on B cells and dendritic cells following activation. In contrast, B7-1 expression is up-regulated later during activation of the immune response on each cell type. However, in the studies described above, B7 expression was examined several weeks after the initial sensitization, which should have been sufficient time for B7-1 expression to be up-regulated. However, as we have previously shown in a similar model that systemic sensitization alone is not sufficient to elicit allergic responses in the lung, the time following local lung challenge with the immunogen may be more critical (8). Alternatively, either the nature of the immunogen, the route of exposure and/or the dose of the immunogen may influence not only the type of immune response but the degree of costimulation required (46, 47).
In summary, our studies provide compelling evidence that the development of Th2 cytokine patterns and subsequent development of allergic airway responses to inhaled Ag challenge requires B7-2 costimulation. As a predominant Th2 cytokine pattern has been observed in human asthmatics (1, 2, 3), these studies suggest that blockade of B7-2 may provide a novel therapeutic approach to the treatment of allergic airway disorders.
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Marsha Wills-Karp, School of Hygiene and Public Health, Johns Hopkins University, 615 N. Wolfe St., Baltimore, MD 21205.
3 Abbreviations used in this paper: BAL, bronchoalveolar lavage; HPRT, hypoxanthine guanine phosphoribosyltransferase.
Received for publication March 17, 1997. Accepted for publication September 30, 1997.
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 A. Al-Shami, R. Spolski, J. Kelly, A. Keane-Myers, and W. J. Leonard A role for TSLP in the development of inflammation in an asthma model J. Exp. Med., September 19, 2005; 202(6): 829 - 839. [Abstract] [Full Text] [PDF]
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P. Rice, E. Martin, J.-R. He, M. Frank, L. DeTolla, L. Hester, T. O'Neill, C. Manka, I. Benjamin, A. Nagarsekar, et al. Febrile-Range Hyperthermia Augments Neutrophil Accumulation and Enhances Lung Injury in Experimental Gram-Negative Bacterial Pneumonia J. Immunol., March 15, 2005; 174(6): 3676 - 3685. [Abstract] [Full Text] [PDF]
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 H-Z Shi, Z-F Xie, J-M Deng, Y-Q Chen, and C-Q Xiao Soluble CD86 protein in serum samples of patients with asthma Thorax, October 1, 2004; 59(10): 870 - 875. [Abstract] [Full Text] [PDF]
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K. Matsumoto, H. Inoue, T. Nakano, M. Tsuda, Y. Yoshiura, S. Fukuyama, F. Tsushima, T. Hoshino, H. Aizawa, H. Akiba, et al. B7-DC Regulates Asthmatic Response by an IFN-{gamma}-Dependent Mechanism J. Immunol., February 15, 2004; 172(4): 2530 - 2541. [Abstract] [Full Text] [PDF]
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A. Iwata, K. Nishio, R. K. Winn, E. Y. Chi, W. R. Henderson Jr., and J. M. Harlan A Broad-Spectrum Caspase Inhibitor Attenuates Allergic Airway Inflammation in Murine Asthma Model J. Immunol., March 15, 2003; 170(6): 3386 - 3391. [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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 D. Ganea and M. Delgado VASOACTIVE INTESTINAL PEPTIDE (VIP) AND PITUITARY ADENYLATE CYCLASE-ACTIVATING POLYPEPTIDE (PACAP) AS MODULATORS OF BOTH INNATE AND ADAPTIVE IMMUNITY Critical Reviews in Oral Biology & Medicine, May 1, 2002; 13(3): 229 - 237. [Abstract] [Full Text] [PDF]
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S.-W. Oh, C. I. Pae, D.-K. Lee, F. Jones, G. K. S. Chiang, H.-O. Kim, S.-H. Moon, B. Cao, C. Ogbu, K.-W. Jeong, et al. Tryptase Inhibition Blocks Airway Inflammation in a Mouse Asthma Model J. Immunol., February 15, 2002; 168(4): 1992 - 2000. [Abstract] [Full Text] [PDF]
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 S. K. Banerjee, H. W. J. Young, J. B. Volmer, and M. R. Blackburn Gene expression profiling in inflammatory airway disease associated with elevated adenosine Am J Physiol Lung Cell Mol Physiol, February 1, 2002; 282(2): L169 - L182. [Abstract] [Full Text] [PDF]
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 M. OKANO, M. AZUMA, T. YOSHINO, H. HATTORI, M. NAKADA, A. R. SATOSKAR, D. A. HARN Jr, E. NAKAYAMA, T. AKAGI, and K. NISHIZAKI Differential Role of CD80 and CD86 Molecules in the Induction and the Effector Phases of Allergic Rhinitis in Mice Am. J. Respir. Crit. Care Med., October 15, 2001; 164(8): 1501 - 1507. [Abstract] [Full Text] [PDF]
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 B. U. Gajewska, F. K. Swirski, D. Alvarez, S. A. Ritz, S. Goncharova, M. Cundall, D. P. Snider, A. J. Coyle, J.-C. Gutierrez-Ramos, M. R. Stampfli, et al. Temporal-Spatial Analysis of the Immune Response in a Murine Model of Ovalbumin-Induced Airways Inflammation Am. J. Respir. Cell Mol. Biol., September 1, 2001; 25(3): 326 - 334. [Abstract] [Full Text] [PDF]
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Z. Liu, K. Geboes, P. Hellings, P. Maerten, H. Heremans, P. Vandenberghe, L. Boon, P. van Kooten, P. Rutgeerts, and J. L. Ceuppens B7 Interactions with CD28 and CTLA-4 Control Tolerance or Induction of Mucosal Inflammation in Chronic Experimental Colitis J. Immunol., August 1, 2001; 167(3): 1830 - 1838. [Abstract] [Full Text] [PDF]
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D. Serebrisky, A. A. Teper, C.-K. Huang, S.-Y. Lee, T.-F. Zhang, B. H. Schofield, M. Kattan, H. A. Sampson, and X.-M. Li CpG Oligodeoxynucleotides Can Reverse Th2-Associated Allergic Airway Responses and Alter the B7.1/B7.2 Expression in a Murine Model of Asthma J. Immunol., November 15, 2000; 165(10): 5906 - 5912. [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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 M. R. Woolhiser, A. E. Munson, and B. J. Meade Immunological Responses of Mice following Administration of Natural Rubber Latex Proteins by Different Routes of Exposure Toxicol. Sci., June 1, 2000; 55(2): 343 - 351. [Abstract] [Full Text] [PDF]
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D. A. Mark, C. E. Donovan, G. T. De Sanctis, H. Z. He, M. Cernadas, L. Kobzik, D. L. Perkins, A. Sharpe, and P. W. Finn B7-1 (CD80) and B7-2 (CD86) Have Complementary Roles in Mediating Allergic Pulmonary Inflammation and Airway Hyperresponsiveness Am. J. Respir. Cell Mol. Biol., March 1, 2000; 22(3): 265 - 271. [Abstract] [Full Text]
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M. Mathur, K. Herrmann, Y. Qin, F. Gulmen, X. Li, R. Krimins, J. Weinstock, D. Elliott, J. A. Bluestone, and P. Padrid CD28 Interactions with Either CD80 or CD86 Are Sufficient to Induce Allergic Airway Inflammation in Mice Am. J. Respir. Cell Mol. Biol., October 1, 1999; 21(4): 498 - 509. [Abstract] [Full Text]
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M. Delgado, J. Leceta, R. P. Gomariz, and D. Ganea Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase-Activating Polypeptide Stimulate the Induction of Th2 Responses by Up-Regulating B7.2 Expression J. Immunol., October 1, 1999; 163(7): 3629 - 3635. [Abstract] [Full Text] [PDF]
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D. C. Tsitoura, R. H. DeKruyff, J. R. Lamb, and D. T. Umetsu Intranasal Exposure to Protein Antigen Induces Immunological Tolerance Mediated by Functionally Disabled CD4+ T Cells J. Immunol., September 1, 1999; 163(5): 2592 - 2600. [Abstract] [Full Text] [PDF]
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A. HACZKU, K. TAKEDA, I. REDAI, E. HAMELMANN, G. CIESLEWICZ, A. JOETHAM, J. LOADER, J. J. LEE, C. IRVIN, and E. W. GELFAND Anti-CD86 (B7.2) Treatment Abolishes Allergic Airway Hyperresponsiveness in Mice Am. J. Respir. Crit. Care Med., May 1, 1999; 159(5): 1638 - 1643. [Abstract] [Full Text] [PDF]
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