Hyperresponsiveness In Mice Research Articles

Para-Bromophenacyl bromide alleviates airway hyperresponsiveness and modulates cytokines, IgE and eosinophil levels in ovalbumin-sensitized and -challenged mice

Airway hyperresponsiveness, airway eosinophilia and increased IgE levels in serum are the important characteristic features of asthma. We evaluated the potential of para-Bromophenacyl bromide (PBPB), a known phospholipase A 2 inhibitor, on allergen-induced airway hyperresponsiveness in a mouse model. We sensitized and challenged mice with ovalbumin (OVA) to develop airway hyperresponsiveness as assessed by airway constriction and airway hyperreactivity (AHR) to methacholine (MCh) induced by allergen. The mice were orally treated with PBPB (0.1, 1 and 10 mg/kg) during or after OVA-sensitization and OVA-challenge to evaluate its protective or reversal effect on airway constriction and AHR to MCh. Determination of OVA-induced airway constriction and AHR to MCh were performed by measuring specific airway conductance (SGaw) using non-invasive dual-chamber whole body-plethysmography. We observed that PBPB (1 mg/kg) significantly reduced OVA-induced airway constriction and AHR to MCh ( p<0.01). PBPB (1 mg/kg) treatment significantly inhibited PLA 2 activity in the BAL fluid. Cytokine analysis of the BAL fluid revealed that PBPB caused an increase in interferon-γ (IFN-γ) ( p<0.02) and a decrease in interleukin-4 (IL-4) ( p<0.05) and interleukin-5 (IL-5) ( p<0.05) levels. The OVA-specific serum IgE levels ( p<0.01) and the BAL eosinophils ( p<0.001) were also reduced significantly. Thus, PBPB is capable of modulating allergen induced cytokine levels and serum IgE levels, and alleviating allergen induced airway hyperresponsiveness and eosinophils in mice. These data suggest that PBPB could be useful in the development of novel agents for the treatment of allergen induced airway hyperresponsiveness.

Airway inflammation and allergen specific IgE production may persist longer than airway hyperresponsiveness in mice.

During the preclinical study of new therapeutic modality, we evaluate whether the treatment can reverse the established asthma phenotypes in animal model. However, few have reported on the long term persistence of asthma phenotypes upon re-challenge with allergen (secondary challenge) in animal model. We evaluated the persistence of asthma phenotypes by secondary challenge at different times in previously challenged murine asthma model. BALB/c mice sensitized by intraperitoneal injections of 20 µgram of ovalbumin and 1 mg of alum on days 1 and 14 were challenged initially by the inhalation of 1% ovalbumin for 30 min on days 21, 22, and 23. Each group of mice was rechallenged at 5, 7, 9, or 12 weeks after the initial challenge. Airway hyperresponsiveness, BAL fluid, airway histology and serum ovalbumin-specific IgE level were evaluated. Airway eosinophilia, airway inflammation and serum ovalbumin-specific IgE production persisted upon secondary allergen challenges at least 12 weeks after the initial challenge. However, airway hyperresponsiveness persisted only until mice were rechallenged 7 weeks after the initial challenge. Airway inflammation and allergen specific IgE production may persist longer than airway hyperresponsiveness in a mouse asthma model of secondary allergen challenge.

The allergic mouse model of asthma: normal smooth muscle in an abnormal lung?

Mice with allergically inflamed airways are widely used as animal models of asthma, but their relevance for human asthma is not understood. We, therefore, examined the time course of changes in respiratory input impedance during induced bronchoconstriction in BALB/c mice sensitized and challenged with ovalbumin. Our results indicate that bronchoconstriction in mice is accompanied by complete closure of substantial regions of the lung and that closure increases markedly when the lungs are allergically inflamed. With the aid of an anatomically accurate computational model of the mouse lung, we show that the hyperresponsiveness of mice with allergically inflamed airways can be explained entirely by a thickening of the airway mucosa and an increased propensity of the airways to close, without the involvement of any increase in the degree of airway smooth muscle shortening. This has implications for the pathophysiology of asthma and suggests that at least some types of asthma may benefit from therapies aimed at manipulating surface tension at the air-liquid interface in the lungs.

Blockade of Inflammation and Airway Hyperresponsiveness in Immune-sensitized Mice by Dominant-Negative Phosphoinositide 3-Kinase–TAT

Phosphoinositide 3-kinase (PI3K) is thought to contribute to the pathogenesis of asthma by effecting the recruitment, activation, and apoptosis of inflammatory cells. We examined the role of class IA PI3K in antigen-induced airway inflammation and hyperresponsiveness by i.p. administration into mice of Δp85 protein, a dominant negative form of the class IA PI3K regulatory subunit, p85α, which was fused to HIV-TAT (TAT-Δp85). Intraperitoneal administration of TAT-Δp85 caused time-dependent transduction into blood leukocytes, and inhibited activated phosphorylation of protein kinase B (PKB), a downstream target of PI3K, in lung tissues in mice receiving intranasal FMLP. Antigen challenge elicited pulmonary infiltration of lymphocytes, eosinophils and neutrophils, increase in mucus-containing epithelial cells, and airway hyperresponsiveness to methacholine. Except for modest airway neutrophilia, these effects all were blocked by treatment with 3–10 mg/kg of TAT-Δp85. There was also significant reduction in IL-5 and IL-4 secretion into the BAL. Intranasal administration of IL-5 caused eosinophil migration into the airway lumen, which was attenuated by systemic pretreatment with TAT-Δp85. We conclude that PI3K has a regulatory role in Th2-cell cytokine secretion, airway inflammation, and airway hyperresponsiveness in mice.

Low-dose carbon monoxide reduces airway hyperresponsiveness in mice.

Carbon monoxide (CO) in expired gas has been shown to be elevated with asthma; however, its function is not known, and there is some potential that it may serve a bronchoprotective role to decrease airway hyperresponsiveness (AHR). Thus the ability of CO to reverse methacholine (MCh)-induced bronchoconstriction was evaluated in C57BL/6 (C57) and A/J mice with and without airway inflammation produced by ovalbumin (OVA). Acutely administered CO (1% in air, 10 min) reduced MCh-driven increases in lung resistance in OVA-challenged C57 mice by an average of 50% (from 14.5 to 7.1 cmH2O.ml-1.s-1), whereas no effect was observed in naïve C57 mice or OVA-challenged C57 mice inhaling air alone. Acutely inhaled CO (500 ppm = 0.05%, for 10 min) reduced MCh-induced airway reactivity (AR) by 20-60% in airway hyperresponsive naïve A/J mice, whereas repeated 10-min administrations of 500 ppm CO over a 5-day period decreased AR by 50%. Repeated administration of low-dose CO [250 (0.025%) and (0.05%) 500 ppm, 1 h/day, 5 days] to A/J mice with airway inflammation likewise resulted in a drop of AR by 50%, compared with those not receiving CO. Inhibition of guanylyl cyclase/guanosine 3',5'-cyclic monophosphothioate (cGMP) using 1H-[1,2,4] oxydiazolo[4,3-a]quinoxalin-1-one or a competitive inhibitor, Rp diastereomers of 8-bromo-cGMP, resulted in inhibition of the effect of CO on AHR, suggesting that the effects of CO were mediated through this mechanism. These results indicate that low-dose CO can effectively reverse AHR in the presence and absence of airway inflammation in mice and suggest a potential role for CO in the modulation of AHR.

Role of immunoglobulin E and mast cells in murine models of asthma.

Immunoglobulin E (IgE) and mast cells are believed to play important roles in allergic inflammation. However, their contributions to the pathogenesis of human asthma have not been clearly established. Significant progress has been made recently in our understanding of airway inflammation and airway hyperresponsiveness through studies of murine models of asthma and genetically engineered mice. Some of the studies have provided significant insights into the role of IgE and mast cells in the allergic airway response. In these models mice are immunized systemically with soluble protein antigens and then receive an antigen challenge through the airways. Bronchoalveolar lavage fluid from mice with allergic airway inflammation contains significant amounts of IgE. The IgE can capture the antigen presented to the airways and the immune complexes so formed can augment allergic airway response in a high-affinity IgE receptor (FcepsilonRI)-dependent manner. Previously, there were conflicting reports regarding the role of mast cells in murine models of asthma, based on studies of mast cell-deficient mice. More recent studies have suggested that the extent to which mast cells contribute to murine models of asthma depends on the experimental conditions employed to generate the airway response. This conclusion was further supported by studies using FcepsilonRI-deficient mice. Therefore, IgE-dependent activation of mast cells plays an important role in the development of allergic airway inflammation and airway hyperresponsiveness in mice under specific conditions. The murine models used should be of value for testing inhibitors of IgE or mast cells for the development of therapeutic agents for human asthma.

Inhibition of allergic airways inflammation and airway hyperresponsiveness in mice by dexamethasone: Role of eosinophils, IL-5, eotaxin, and IL-13

Background: Glucocorticoids inhibit allergen-induced airway eosinophilia and airway hyperresponsiveness (AHR). Whether glucocorticoids mediate their effects on AHR by inhibiting eotaxin and IL-5, 2 of the principal mediators of eosinophilia, or through IL-13, an important mediator of AHR, has not been established. Objective: We sought to investigate the effects of glucocorticoids on airway eosinophilia and the expression of IL-5, eotaxin, and IL-13 in relation to the induction of AHR in a murine model of allergic asthma. Methods: Dexamethasone (4 mg/kg) and mAbs against eotaxin (80 μg/kg) and IL-5 (100 μg/kg) singly and in combination were administered to immunized mice before antigen challenge. Airway responsiveness to methacholine was measured in anesthetized and mechanically ventilated animals. Eotaxin, IL-5, and IL-13 in bronchoalveolar lavage fluid (BALF), lung homogenates, or both were measured by means of ELISA. Results: A single antigen challenge induced AHR that lasted at least 10 days. Eotaxin protein and mRNA levels increased in lung tissue but not in BALF after challenge. IL-5 protein and mRNA levels increased both in BALF and in lung tissue. Dexamethasone reduced airway eosinophilia, AHR, and protein and mRNA for eotaxin and IL-5. Anti-murine eotaxin and anti-IL-5 antibodies alone and in combination reduced the ovalbumin-induced airway eosinophilia significantly but failed to inhibit AHR. Both dexa-methasone and anti-IL-5/anti-eotaxin inhibited the increases in lung IL-13 levels after ovalbumin challenge to a similar extent. Conclusion: These findings suggest that the inhibition of AHR by the glucocorticoid dexamethasone does not appear to be explained by effects on eosinophilia, eotaxin, IL-5, or IL-13. (J Allergy Clin Immunol 2003;111:1049-61.)

The role of the mast cell in asthma: a reassessment

Interest in the role of the mast cell in bronchial asthma has waxed and waned over several decades, but there is now compelling evidence that mast cells make an important contribution to the pathophysiology of this disease. This review will discuss current advances in this field. Mast cells, but not T cells or eosinophils, localize within the bronchial smooth muscle bundles in patients with asthma but not in normal individuals or those with eosinophilic bronchitis. Smooth muscle mast cell density correlates significantly with indices of bronchial hyperresponsiveness, and is likely to be an important factor determining the asthmatic phenotype. Tryptase induces proliferation in human airway smooth muscle, and the recently identified transmembrane form induces the development of bronchial hyperresponsiveness in mice. IL-4 and IL-13, known mast cell products, also induce bronchial hyperresponsiveness in the mouse, in the absence of an inflammatory response. There are therefore several pathways by which the close approximation of mast cells with airway smooth muscle cells might lead to disordered smooth muscle function. Mast cells also infiltrate the airway mucous glands in patients with asthma, showing features of degranulation, and a positive correlate with the amount of mucus obstructing the airway lumen. Taken together these observations suggest that mast cells also play an important role in regulating mucous gland secretion. The development of potent and specific inhibitors of mast cell secretion, which remain active when administered long term to asthmatic airways, should offer a novel approach to the treatment of asthma.

World Trade Center fine particulate matter causes respiratory tract hyperresponsiveness in mice.

Pollutants originating from the destruction of the World Trade Center (WTC) in New York City on 11 September 2001 have been reported to cause adverse respiratory responses in rescue workers and nearby residents. We examined whether WTC-derived fine particulate matter [particulate matter with a mass median aerodynamic diameter < 2.5 microm (PM2.5)] has detrimental respiratory effects in mice to contribute to the risk assessment of WTC-derived pollutants. Samples of WTC PM2.5 were derived from settled dust collected at several locations around Ground Zero on 12 and 13 September 2001. Aspirated samples of WTC PM2.5 induced mild to moderate degrees of pulmonary inflammation 1 day after exposure but only at a relatively high dose (100 microg). This response was not as great as that caused by 100 microg PM2.5 derived from residual oil fly ash (ROFA) or Washington, DC, ambient air PM [National Institute of Standards and Technology, Standard Reference Material (SRM) 1649a]. However, this same dose of WTC PM2.5 caused airway hyperresponsiveness to methacholine aerosol comparable to that from SRM 1649a and to a greater degree than that from ROFA. Mice exposed to lower doses by aspiration or inhalation exposure did not develop significant inflammation or hyperresponsiveness. These results show that exposure to high levels of WTC PM2.5 can promote mechanisms of airflow obstruction in mice. Airborne concentrations of WTC PM2.5 that would cause comparable doses in people are high (approximately 425 microg/m3 for 8 hr) but conceivable in the aftermath of the collapse of the towers when rescue and salvage efforts were in effect. We conclude that a high-level exposure to WTC PM2.5 could cause pulmonary inflammation and airway hyperresponsiveness in people. The effects of chronic exposures to lower levels of WTC PM2.5, the persistence of any respiratory effects, and the effects of coarser WTC PM are unknown and were not examined in these studies. Degree of exposure and respiratory protection, individual differences in sensitivity to WTC PM2.5, and species differences in responses must be considered in assessing the risks of exposure to WTC PM2.5.

Selective cyclooxygenase-1 and -2 inhibitors each increase allergic inflammation and airway hyperresponsiveness in mice.

Nonselective cyclooxygenase (COX) inhibition during allergic sensitization with ovalbumin in a murine model leads to an increase in the Type 2 cytokines interleukin-5 (IL-5) and IL-13; however, the effect of selective COX-1 and COX-2 inhibitors on these cytokines is unknown. We found that COX-1 protein was constitutively expressed in lung tissue. Expression of COX-1 protein did not increase with ovalbumin sensitization, but expression of COX-2 protein did. Ovalbumin-sensitized mice treated with either selective COX-1 inhibitor SC58560 (OVA-COX-1 inhibitor) or selective COX-2 inhibitor SC58236 (OVA-COX-2 inhibitor) had significantly greater airway hyperresponsiveness (p < 0.05) and higher levels of IL-13 (p < 0.05) in lung supernatants than did untreated mice that were ovalbumin sensitized (OVA). Lung mRNA levels for the chemokine receptors CCR1 through CCR5 (expressed on eosinophils, basophils, lymphocytes, and dendritic cells) were increased in the OVA-COX-2 inhibitor and OVA-indomethacin groups. We conclude that in the BALB/c mouse, COX inhibition with either a COX-1 or COX-2 inhibitor during allergen sensitization augments production of IL-13 and increases airway hyperresponsiveness.

Effects of birch pollen and traffic particulate matter on Th2 cytokines, immunoglobulin E levels and bronchial hyper-responsiveness in mice.

Health effects due to air pollution arising from motor vehicles are a major public and political concern world-wide. Epidemiological studies have shown that the manifestations of asthma are increased by air pollution in already affected individuals. To investigate the potential role of air-polluted tunnel dust (traffic particulate matter, TPM) or pure carbon core particles in the initiation and persistence of experimental allergic inflammation. BP2 mice were immunized with birch pollen alone (group B) or pollen together with TPM (group A), or with birch pollen and Al(OH)3 (group C), or with birch pollen and carbon core particles (group D). Before methacholine challenge they were challenged intranasally and thereafter bronchial hyper-reactivity (BHR) was evaluated in a whole-body plethysmograph. Levels of Th2 cytokines, fibronectin and lactate dehydrogenase (LDH) were determined, and differential counts were performed in the bronchoalveolar lavage (BAL) fluid. Sera were collected for determination of antibody titres and cytokine levels. Specific IgE titres, BHR, the number of recruited eosinophils and levels of fibronectin and LDH in BAL were increased in mice immunized and challenged with a mixture of birch pollen and TPM. However, mice immunized with birch pollen alone and challenged intranasally with pollen or a mixture of pollen and TPM demonstrated the highest levels of IL-4 and IL-5. This study highlights the importance of the exposure to a combination of particulate matters and pollen allergens, in the induction of allergic disease in the airways, and we have demonstrated that polluted tunnel dust has an effect on both the inflammatory and immunological components of experimental allergy. Immunization and challenge with carbon core particles together with birch pollen increased neither the BHR nor the specific IgE production significantly. Our results therefore strongly suggest that it is most likely to be the organic phase bound to the carbon core of the diesel exhaust particles that might have an important adjuvant effect in the induction of experimental allergy.

Nitrate and nitrite in exhaled breath condensate are derived from the lower airway

Nitrate and nitrite in exhaled breath condensate are derived from the lower airway

Tumor necrosis factor receptor 2 contributes to ozone-induced airway hyperresponsiveness in mice.

The purpose of this study was to determine whether tumor necrosis factor (TNF) contributes to airway hyperresponsiveness (AHR) and migration of polymorphonuclear leukocytes (PMN) into the airways following exposure to ozone (O(3)). Wild-type mice, TNF p55 or p75 receptor knockout mice (p55 TNFR -/- and p75 TNFR -/-), as well as double receptor knockout mice (p55/p75 TNFR -/-), were exposed to O(3). Three hours after cessation of O(3), airway responses to inhaled methacholine were determined by whole body plethysmography using changes in enhanced pause (Penh) as an index of airway narrowing. In wild-type mice, O(3) exposure (0.5 ppm, 3 h) caused a significant increase in airway responsiveness as indicated by a 1.2 log leftward shift in the methacholine dose- response curve. In contrast, in p55/p75 TNFR -/- mice, O(3) caused only a 0.5 log shift in the dose-response curve (p < 0.05 compared with wild-type). Similar results were obtained in p75 TNFR -/- mice. In contrast, O(3)-induced airway hyperresponsiveness was not different in WT and p55 TNFR -/- mice. During O(3) exposure (1 pm, 3 h), minute ventilation (V E) decreased by 64 +/- 4% in wild-type, but only 24 +/- 5% in p55/p75 TNFR -/- mice, indicating that despite their reduced O(3)-induced AHR, the TNFR-deficient mice actually inhaled a greater dose of O(3). Similar results were obtained in p75 -/- mice, whereas changes in V E induced by O(3) were the same in wild-type and p55 -/- mice. PMN numbers in bronchoalveolar lavage fluid recovered 21 h after cessation of exposure to O(3) (2 ppm, 3 h) were significantly increased compared with after air exposure but were not different in wild-type and p55/p75 TNFR -/- mice. Our results indicate that TNF contributes to the AHR but not the PMN emigration induced by acute O(3) exposure. whole body plethysmography; polymorphonuclear leukocytes; minute ventilation; knockout mice; methacholine

Tidal midexpiratory flow as a measure of airway hyperresponsiveness in allergic mice.

A method for the noninvasive measurement of airway responsiveness was validated in allergic BALB/c mice. With head-out body plethysmography and the decrease in tidal midexpiratory flow (EF(50)) as an indicator of airway obstruction, responses to inhaled methacholine (MCh) and the allergen ovalbumin were measured in conscious mice. Allergen-sensitized and -challenged mice developed airway hyperresponsiveness as measured by EF(50) to aerosolized MCh compared with that in control animals. This response was associated with increased allergen-specific IgE and IgG1 production, increased levels of interleukin-4 and interleukin-5 in bronchoalveolar lavage fluid and eosinophilic lung inflammation. Ovalbumin aerosol challenge elicited no acute bronchoconstriction but resulted in a significant decline in EF(50) baseline values 24 h after challenge in allergic mice. The decline in EF(50) to MCh challenge correlated closely with simultaneous decreases in pulmonary conductance and dynamic compliance. The decrease in EF(50) was partly inhibited by pretreatment with the inhaled beta(2)-agonist salbutamol. We conclude that measurement of EF(50) to inhaled bronchoconstrictors by head-out body plethysmography is a valid measure of airway hyperresponsiveness in mice.

Nerve Growth Factor Induces Airway Hyperresponsiveness in Mice

Background: Previous studies indicated an upregulation of nerve growth factor (NGF) production during allergic inflammation. However, the function of NGF in the lungs is currently poorly understood. It was suggested that NGF could play an important role in the pathophysiology of airway hyperresponsiveness. The regulatory network between immunological events and altered neuronal control of airway smooth muscle contractility remains to be defined. Methods: NGF was delivered into the airways of mice either by nasal instillation or by genetic engineering. Airway reactivity was then measured by electrical field stimulation. Results: Treatment of mice with NGF induced airway hyperresponsiveness to a similar extent as demonstrated in allergen-sensitized mice. NGF-transgenic mice, overexpressing NGF in Clara cells, were hyperreactive in comparison to wild-type mice. Conclusion: These data suggest that NGF by itself determines the induction of airway hyperresponsiveness in the absence of airway inflammation in mice.

Intervention of thymus and activation-regulated chemokine attenuates the development of allergic airway inflammation and hyperresponsiveness in mice.

Thymus- and activation-regulated chemokine (TARC; CCL17) is a lymphocyte-directed CC chemokine that specifically chemoattracts CC chemokine receptor 4-positive (CCR4(+)) Th2 cells. To establish the pathophysiological roles of TARC in vivo, we investigated here whether an mAb against TARC could inhibit the induction of asthmatic reaction in mice elicited by OVA. TARC was constitutively expressed in the lung and was up-regulated in allergic inflammation. The specific Ab against TARC attenuated OVA-induced airway eosinophilia and diminished the degree of airway hyperresponsiveness with a concomitant decrease in Th2 cytokine levels. Our results for the first time indicate that TARC is a pivotal chemokine for the development of Th2-dominated experimental allergen-induced asthma with eosinophilia and AHR. This study also represents the first success in controlling Th2 cytokine production in vivo by targeting a chemokine.

Tumor necrosis factor receptor 2 contributes to ozone-induced airway hyperresponsiveness in mice

Tumor necrosis factor receptor 2 contributes to ozone-induced airway hyperresponsiveness in mice

Respiratory syncytial virus infection does not increase allergen-induced type 2 cytokine production, yet increases airway hyperresponsiveness in mice

Severe respiratory syncytial virus (RSV)-induced disease is associated with childhood asthma and atopy. We combined murine models of allergen-sensitization and RSV infection to explore the interaction of allergic and virus-induced airway inflammation and its impact on airway hyperresponsiveness (AHR). We found that RSV infection during ova-sensitization (OVA/RSV) increased and prolonged AHR compared to mice only RSV-infected (RSV) or ova-sensitized (OVA). AHR is known to be associated with an increase in Type 2 cytokines (IL-4, IL-5, and IL-13) in allergen-sensitized mice. Therefore, we hypothesized that RSV-induced enhancement of AHR was a result of potentiating the Type 2 cytokine profile promoted by ova-sensitization. Surprisingly, we found that Type 2 cytokines induced by ova-sensitization were not increased by RSV infection despite the increase in AHR, and in some cases were diminished. RNAse protection assay revealed no difference in IL-4 and IL-5 mRNA levels between the OVA and OVA/RSV groups, and IL-13 mRNA was significantly decreased in the OVA/RSV mice compared to the OVA group. Flow cytometric analysis of Type 2 cytokines demonstrated the same frequency of IL-4 and IL-5 production in lung-derived T lymphocytes from the OVA/RSV and OVA groups. Direct cytokine ELISA measurements of lung supernatant showed the level of IL-13 was significantly decreased in the OVA/RSV group compared to OVA mice, while there was no difference in either IL-4 or IL-5 between these two groups. These data indicate that the enhanced and prolonged AHR caused by the interaction of allergic airway inflammation and virus-induced immune responses is a complex process that can not be explained simply by augmented production of Type 2 cytokines.

CD40L, but not CD40, is required for allergen-induced bronchial hyperresponsiveness in mice.

Asthma is characterized by immunoglobulin (Ig) E production, infiltration of the respiratory mucosa by eosinophils (EOSs) and mononuclear cells, and bronchial hyperresponsiveness (BHR). Interaction of CD40 on B cells and antigen presenting cells, with its ligand (CD40L) expressed transiently on activated T cells, is known to augment both T cell-driven inflammation and humoral immune responses, especially IgE production. Considering both the prominent role of inflammation in asthma and the association of the disease with IgE, we hypothesized that CD40-CD40L interactions would be important in pathogenesis. To test this hypothesis, we subjected wild-type (WT) mice and animals lacking either CD40 or CD40L to repeated inhalation of Aspergillus fumigatus (Af ) antigen. Af-treated WT mice displayed elevated IgE levels, bronchoalveolar lavage and pulmonary tissue eosinophilic inflammation, and BHR. IgE production was markedly suppressed in both the CD40 -/- and CD40L -/- strains. However, pulmonary inflammation did not appear to be inhibited by either of these mutations. Paradoxically, development of BHR was prevented by the lack of CD40L but not by the absence of CD40. We conclude that CD40/CD40L interactions, although critical in the induction of IgE responses to inhaled allergen, are not required for the induction of EOS-predominant inflammation. CD40L, but not CD40, is necessary for the development of allergen-induced BHR.

Respiratory syncytial virus (RSV)-induced airway hyperresponsiveness in allergically sensitized mice is inhibited by live RSV and exacerbated by formalin-inactivated RSV.

Respiratory syncytial virus (RSV)-induced disease is associated with recurrent episodes of wheezing in children, and an effective vaccine currently is not available. The use of 2 immunizations (a formalin-inactivated, alum-precipitated RSV vaccine [FI-RSV] given intramuscularly and live RSV given intranasally [LVIN]), with a control immunization, were compared in a well-characterized model of RSV challenge, with or without concomitant allergic sensitization with ovalbumin. FI-RSV caused a significant increase in airway hyperresponsiveness in mice after RSV infection during allergic sensitization, and this was associated with an increase in type 2 cytokine production. In contrast, immunization with LVIN did not change type 2 cytokine production and protected against RSV-induced airway hyperresponsiveness in the setting of allergic sensitization. This study suggests that immune modulation with RSV vaccination can have profound effects on RSV-induced airway disease and that prevention of airway hyperresponsiveness is an important end point in vaccine development.