Allergen-induced airway hyperresponsiveness

Allergen inhalation in the laboratory can lead to an early (0 to 2 hours) and late (3 to 12 hours) asthmatic response and an increase in airway hyperresponsiveness to a variety of bronchoconstrictor mediators. Also, environmental allergen exposure increases airway responsiveness, symptoms of asthma, and the amount of treatment needed to control symptoms. Allergen inhalation causes an acute inflammatory response with an influx of predominantly neutrophils and/or eosinophils into the airway in both animal preparations and sensitized human subjects. The development of airway hyperresponsiveness is most likely a consequence of the inflammatory response. The mediators involved in initiating the inflammatory response or airway hyperresponsiveness have not yet been clearly identified. However, potent chemotactic factors, such as leukotriene B4 and platelet-activating factor can initiate both airway inflammation and airway hyperresponsiveness. In addition, in some animal preparations, cyclooxygenase products of arachidonate metabolism, possibly thromboxane, play a central role in the pathogenesis of airway hyperresponsiveness after inhalation of inflammatory stimuli such as allergen.     

Der p 1 and Der p 2 induce less severe late asthmatic responses than native Dermatophagoides pteronyssinus extract after a similar early asthmatic response

Background The models for exposure to house dust in research and clinical practice are selected with respect to their role in IgE‐mediated immediate hypersensitivity. The use of isolated major allergens instead of complex allergen extracts is becoming increasingly popular as it offers some important advantages for quantitative measures in diagnosis and research. Objective To compare house dust mite extract and isolated mite major allergens with respect to their ability to induce early and late asthmatic responses and bronchial hyperreactivity. Methods Bronchial responses to house dust mite (HDM, Dermatophagoides pteronyssinus) extract and isolated major allergens from HDM (Der p 1 and Der p 2) were compared in a double‐blind, randomized, cross‐over study in 20 patients with mild to moderate asthma who were allergic to HDM. Allergen was titrated to a standardized early asthmatic response. Bronchial hyper‐responsiveness to histamine (PC₂₀histamine) was determined before and after allergen inhalation to assess allergen‐induced bronchial hyper‐responsiveness and IL‐5 was measured in serum. In addition, the allergens were applied in intracutaneous skin tests and activation of basophil leucocytes and proliferation of peripheral blood mononuclear cells was tested in vitro. Results After a similar early asthmatic response (mean Δforced expiratory volume in 1 s (FEV₁)_,max?29.4 (SD 7.2) vs. ?33.1 (8.6) %; mean difference 3.6 (95% CI ?0.9 to 8.2) %), the late asthmatic response (mean ΔFEV_1,max?45.9 (21.9) vs. ?32.7 (22.3) %; mean difference 13.2 (3.8–22.3) %), the degree of allergen‐induced bronchial hyper‐responsiveness (mean ΔPC₂₀histamine, 1.8 (1.0) vs. 1.2 (0.9) doubling dose; mean difference 0.6 (0.2–1.1) doubling dose) and serum IL‐5 at 6 h were found to be significantly higher after bronchial challenge with HDM extract than after challenge with an isolated HDM major allergen. Likewise, there was an increased late skin reaction with HDM compared with isolated major allergen after a similar early skin reaction. Conclusion Constituents of HDM extract, other than Der p 1 or Der p 2, with no significant influence on the IgE‐mediated early asthmatic response contribute significantly to the allergen‐induced late asthmatic response and bronchial hyper‐reactivity.     

Allergen-induced airway inflammation and its therapeutic intervention

Allergen inhalation challenge has been useful for examining the mechanisms of allergen-induced airway inflammation and the associated physiological changes and for documenting the efficacy of drugs to treat asthma. Allergen inhalation by a sensitized subject results in acute bronchoconstriction, beginning within 15-30 min and lasting 1-3 hr, which can be followed by the development of a late asthmatic response. Individuals who develop both an early and late response after allergen have more marked increases in airway hyperresponsiveness, and greater increases in allergen-induced airway inflammation, particularly in airway eosinophils and basophils. All of the currently available and effective treatments for asthma modify some aspects of allergen-induced responses. These medications include short-acting and long-acting inhaled β₂-agonists, inhaled corticosteroids, cromones, methylxanthines, leukotriene inhibitors, and anti-IgE monoclonal antibody. In addition, allergen inhalation challenge has become a useful method which can, in a very limited number of patients, provide key information on the therapeutic potential of new drugs being developed to treat asthma.     

Toll‐like receptor 4 agonists adsorbed to aluminium hydroxide adjuvant attenuate ovalbumin‐specific allergic airway disease: role of MyD88 adaptor molecule and interleukin‐12/interferon‐γ axis

Background Epidemiological and experimental data suggest that bacterial lipopolysaccharides (LPS) can either protect from or exacerbate allergic asthma. Lipopolysaccharides trigger immune responses through toll‐like receptor 4 (TLR4) that in turn activates two major signalling pathways via either MyD88 or TRIF adaptor proteins. The LPS is a pro‐Type 1 T helper cells (Th1) adjuvant while aluminium hydroxide (alum) is a strong Type 2 T helper cells (Th2) adjuvant, but the effect of the mixing of both adjuvants on the development of lung allergy has not been investigated. Objective We determined whether natural (LPS) or synthetic (ER‐803022) TLR4 agonists adsorbed onto alum adjuvant affect allergen sensitization and development of airway allergic disease. To dissect LPS‐induced molecular pathways, we used TLR4‐, MyD88‐, TRIF‐, or IL‐12/IFN‐γ‐deficient mice. Methods Mice were sensitized with subcutaneous injections of ovalbumin (OVA) with or without TLR4 agonists co‐adsorbed onto alum and challenged with intranasally with OVA. The development of allergic lung disease was evaluated 24 h after last OVA challenge. Results Sensitization with OVA plus LPS co‐adsorbed onto alum impaired in dose‐dependent manner OVA‐induced Th2‐mediated allergic responses such as airway eosinophilia, type‐2 cytokines secretion, airway hyper‐reactivity, mucus hyper production and serum levels of IgE or IgG1 anaphylactic antibodies. Although the levels of IgG2a, Th1‐affiliated isotype increased, investigation into the lung‐specific effects revealed that LPS did not induce a Th1 pattern of inflammation. Lipopolysaccharides impaired the development of Th2 immunity, signaling via TLR4 and MyD88 molecules and via the IL‐12/IFN‐γ axis, but not through TRIF pathway. Moreover, the synthetic TLR4 agonists that proved to have a less systemic inflammatory response than LPS also protected against allergic asthma development. Conclusion Toll‐like receptor 4 agonists co‐adsorbed with allergen onto alum down‐modulate allergic lung disease and prevent the development of polarized T cell‐mediated airway inflammation.     

Role of prostaglandin D2/CRTH2 pathway on asthma exacerbation induced by Aspergillus fumigatus

Aspergillus fumigatus is often associated in asthmatic patients with the exacerbation of asthma symptoms. The pathomechanism of this phenomenon has not been fully understood. Here, we evaluated the immunological mechanisms and the role of the prostaglandin D₂/ Chemoattractant Receptor‐Homologous Molecule Expressed on Th2 Cells (CRTH2) pathway in the development of Aspergillus‐associated asthma exacerbation. We studied the effects of A. fumigatus on airway inflammation and bronchial hyper‐responsiveness in a rat model of chronic asthma. Inhalation delivery of A. fumigatus conidia increased the airway eosinophilia and bronchial hyper‐responsiveness in ovalbumin‐sensitized, challenged rats. These changes were associated with prostaglandin D₂ synthesis and CRTH2 expression in the lungs. Direct inflammation occurred in ovalbumin‐sensitized, challenged animals, whereas pre‐treatment with an antagonist against CRTH2 nearly completely eliminated the A. fumigatus‐induced worsening of airway eosinophilia and bronchial hyper‐responsiveness. Our data demonstrate that production of prostaglandin D₂ followed by eosinophil recruitment into the airways via a CRTH2 receptor are the major pathogenic factors responsible for the A. fumigatus‐induced enhancement of airway inflammation and responsiveness.     

Allergen inhalation challenge in smoking compared with non‐smoking asthmatic subjects

Background Smoking asthmatics experience more severe symptoms, require more rescue medication and have more asthma‐related hospitalizations than non‐smoking asthmatics. However, studies in mice suggest that mainstream cigarette smoke may reduce airway inflammation and may attenuate airway hyperresponsiveness. A comparison of allergen‐induced airway inflammatory responses of smoking and non‐smoking atopic asthmatics has not been examined previously. Objectives To determine whether allergen‐induced airway responses and inflammatory profiles are attenuated in smoking when compared with non‐smoking mild allergic asthmatic subjects. Methods Allergen inhalation challenges were performed in 13 smoking and 19 non‐smoking mild allergic asthmatic subjects. The forced expired volume in 1 s (FEV₁) was measured up to 7 h after allergen inhalation. Methacholine airway responsiveness was measured before and at 24 h after allergen and sputum was induced before and at 7 and 24 h after allergen. Results Both the smoking and non‐smoking groups developed similar allergen‐induced falls in FEV₁ during the early and late asthmatic responses and similar increases in allergen‐induced airway eosinophils. The mean maximum fall in FEV₁ during the late response was 16.3±4.3% in non‐smokers and 12.9±7.2% in smokers. The smoking asthmatics, however, did not develop allergen‐induced methacholine airway hyperresponsiveness, whereas the non‐smoking controls developed a 1.18 doubling dose shift in methacholine PC₂₀ (P<0.05). Conclusions and Clinical Relevance Mild allergic asthmatic subjects, who were current smokers with a mean 6‐year pack history, develop allergen‐induced eosinophilic airway inflammation and late responses, similar in magnitude to non‐smoking asthmatics, but do not develop methacholine airway hyperresponsiveness associated with the allergen‐induced airway eosinophilia. Cite this as: Z. Meghji, B. Dua, R. M. Watson, G. M. Gauvreau and P. M. O'Byrne, Clinical & Experimental Allergy, 2011 (41) 1084–1090.     

Bronchial hyperresponsiveness and airway wall remodelling induced by exposure to allergen for 9 weeks.

Prolonged exposure to allergen has been proposed to be important for the development of bronchial hyperresponsiveness and airway remodelling in asthma. The present study was designed to examine the effect of chronic allergen exposure on bronchial responsiveness, eosinophil infiltration, and airway remodelling. We sensitized brown Norway rats with the occupational allergen trimellitic anhydride (TMA) and exposed the animals to TMA conjugated to rat serum albumin (TMA-RSA) on 5 consecutive days each week for 9 weeks, starting 4 weeks after sensitization. IgE and IgG anti-TMA antibodies in serum and bronchial responsiveness to acetylcholine were evaluated before and at weeks 3, 6, and 9 of allergen exposure. Thickness of the airway wall, airway luminal narrowing, and the number of goblet cells and eosinophils in the airway wall were evaluated with an image analysis system in lungs resected after the last assessment of bronchial responsiveness, at the end of the 9-week allergen exposure. All rats developed IgE and IgG anti-TMA antibodies after sensitization. The levels of antibodies increased with allergen exposure until week 6, and then declined. Bronchial hyperresponsiveness to acetylcholine was induced in allergen-exposed rats without ongoing airway eosinophilia. Bronchial hyperresponsiveness induced by chronic allergen exposure via inhalation was accompanied by significantly increased thickness of smooth muscle and airway narrowing in the small airways, and goblet cell hyperplasia in the large airways. We conclude that chronic exposure to allergen can induce bronchial hyperresponsiveness and airway wall remodelling. Airway wall remodelling may contribute to bronchial hyperresponsiveness.     

Time‐dependent distinct roles of Toll‐like receptor 4 in a house dust mite‐induced asthma mouse model

House dust mites (HDM s) are a common source of allergens that trigger both allergen‐specific and innate immune responses in humans. Here, we examined the effect of allergen concentration and the involvement of Toll‐like receptor 4 (TLR 4) in the process of sensitization to house dust mite allergens in an HDM extract‐induced asthma mouse model. Intranasal administration of HDM extract induced an immunoglobulin E response and eosinophilic inflammation in a dose‐dependent manner from 2.5 to 30 μg/dose. In TLR 4‐knockout mice, the infiltration of eosinophils and neutrophils into the lung was decreased compared with that in wild‐type mice in the early phase of inflammation (total of three doses). However, in the late phase of inflammation (total of seven doses), eosinophil infiltration was significantly greater in TLR 4‐knockout mice than in wild‐type mice. This suggests that the roles of TLR 4 signaling are different between the early phase and the later phase of HDM allergen‐induced inflammation. Thus, innate immune response through TLR 4 regulated the response to HDM allergens, and the regulation was altered during the phase of inflammation.     

Appearance of allergen-induced increases in airway responsiveness only after repeated allergen inhalations in two subjects

Observations in two subjects undergoing three allergen challenges for a drug study suggested 'priming' of the late sequelae, namely allergen-induced increase in airway responsiveness. Both subjects had rhinitis and asthma limited to the ragweed season, near normal out-of-season histamine PC20, and extreme IgE sensitivity to ragweed. Both had an isolated early response with no change in histamine PC20 after the first allergen challenge. Significant (3.5- to 5.8-fold) reductions in histamine PC20 occurred after the second and third allergen challenge in Subject 1, and after the third challenge in Subject 2; this was associated with equivocal 5-8% late responses. Such a 'priming' effect, the prevalence of which is not known, may be important in the pathogenesis of naturally occurring allergic asthma, and in the design of clinical trials involving repeated allergen inhalations.     

Late asthmatic responses induced by ragweed pollen allergen

Allergen inhalation tests with ragweed pollen extract were performed in 15 ragweed-allergic asthmatic subjects. Isolated early asthmatic responses were induced in 6 subjects, dual (early and late) responses in 8 subjects, and predominantly or isolated late responses in 1 subject. The frequency and magnitude of late asthmatic responses (LAR) indicate that they are important in the disease. LAR occurred in the more sensitive subjects; in general, these subjects required smaller doses of inhaled ragweed pollen extracts, exhibited larger skin test responses, and had higher serum levels of IgE antibodies to ragweed antigen E. Intradermal tests with ragweed pollen extract elicited early (wheal and flare) or dual (early followed by late) cutaneous allergic responses. With relatively large concentrations of injected ragweed allergen, dual responses could be elicited in virtually all subjects.     

Challenge with environmental tobacco smoke exacerbates allergic airway disease in human beings

BACKGROUND: Despite widespread perceptions that environmental tobacco smoke (ETS) is a potent risk factor for allergic airway disease, epidemiologic studies studying this have been equivocal. There is a clear need for experimental studies to address these questions. OBJECTIVE: We directly tested the hypothesis that ETS could interact with allergen in human beings to alter immune responses and promote changes associated with allergic airway disease. METHODS: In a randomized, placebo-controlled crossover study, 19 nonsmoking volunteers with ragweed allergy underwent nasal lavage followed by controlled chamber exposures to 2 hours ETS or clean air followed by another nasal lavage. Subjects immediately randomly received nasal challenge with either ragweed allergen or placebo (300 microL saline). Lavages were also performed 10 minutes, 24 hours, and 4 and 7 days after challenge and IgE, cytokines, and histamine measured. The other arms of the study were spaced at least 6 weeks apart. RESULTS: Environmental tobacco smoke promoted the production of allergen-specific IgE, the hallmark of allergic disease in nasal lavage fluid. Four days after exposure to ETS/ragweed, levels were on average 16.6-fold higher than after clean air/ragweed challenge. In addition, ETS (vs air) promoted the induction of a T(H)2-cytokine nasal milieu (increased IL-4, IL-5, and IL-13 and decreased IFN-gamma production), characteristic of an active allergic response. Moreover, nasal histamine levels were 3.3-fold greater after ETS/ragweed challenge than after clean air/ragweed challenge. CONCLUSION: These studies provide the first experimental evidence that secondhand smoke can exacerbate allergic responses in human beings. CLINICAL IMPLICATIONS: The studies suggest that patients with allergies should avoid tobacco smoke.     

CD‐sens: a biological measure of immunological changes stimulated by ASIT

Background: Allergen‐specific immunotherapy (ASIT) in allergic rhinitis and asthma is the only treatment that effects the long‐term development of these diseases. Basophil allergen threshold sensitivity, CD‐sens, which is a valuable complement to resource‐demanding clinical challenge tests, was used to monitor the initiation of ASIT induced allergen ‘blocking activity’. Methods: Patients IgE‐sensitized to timothy (n = 14) or birch (n = 19) pollen were started on conventional (8–16 weeks) or ultra rush ASIT, respectively, and followed by measurements of CD‐sens, allergen binding activity (ABA) and serum IgG4‐ and IgE‐antibody concentrations. Results: CD‐sens decreased during the early phase of ASIT‐treatment. In parallel, ABA increased and correlated significantly with the increasing levels of IgG4 antibody concentrations. High dosages of allergen were more effective while mode of dosing up did not seem to matter. No change was seen in basophil reactivity. Conclusion: CD‐sens and ABA, in contrast to basophil reactivity, seem to be promising tools to monitor protective immune responses initiated by ASIT.     

Components of airway hyperresponsiveness and their associations with inflammation and remodeling in mice

BACKGROUND: Pathologic changes, including inflammation and remodeling, occur in the asthmatic airway. However, their relative contribution to the components of airway hyperresponsiveness (AHR) remains unclear. OBJECTIVE: Attempting to delineate AHR into discrete immune-mediated and structural remodeling components, we performed a detailed time course of the development, progression, and persistence of maximal respiratory system resistance, airway reactivity, and airway sensitivity. METHODS: Mice exposed to increasing durations of persistent allergen were assessed for airway function, morphometry, and inflammation. RESULTS: Allergen exposure resulted in increases for all indices of AHR that persisted for at least 4 weeks after chronic allergen exposure (P < .01 for all values). Early increases in AHR were associated with increases in immune-mediated events, including airway eosinophils (P < .01), whereas sustained AHR was associated with structural remodeling events. Increased maximal respiratory system resistance, evident by 6 weeks postallergen and persisting for at least 4 weeks after 8 weeks of chronic exposure, was associated with an increase in collagen deposition (P < .01). Increased airway reactivity and sensitivity, each evident by 1 week after allergen and persisting for at least 4 weeks after 8 weeks of chronic exposure, were associated with an increase in airway smooth muscle area (P < .01). CONCLUSION: Our novel observation of distinct temporal relationships in the development, progression, and persistence of the individual indices of AHR supports our hypothesis that multiple underlying factors contribute to airway dysfunction. CLINICAL IMPLICATIONS: These findings illustrate the importance of clearly addressing specific components of airway dysfunction to provide greater insight into specific pathophysiologic mechanisms in airway disease.     

Relationship between cutaneous allergen response and airway allergen-induced eosinophilia

BACKGROUND: Determinants of changes in airway caliber after allergen challenge include nonallergic airway responsiveness, immune response and dose of allergen given. However, determinants of the airway inflammatory response to allergens remain to be determined. AIM: To assess the relationship between skin reactivity to airborne allergens and lower airway eosinophilic response to allergen exposure in asthma and allergic rhinitis. METHODS: Forty-two subjects with mild allergic asthma (mean age 24 years) and 14 nonasthmatic subjects with allergic rhinitis (mean age 25 years) had allergen skin prick tests and titration with the allergen chosen for subsequent challenge. On a second visit, 31 asthmatic subjects had a conventional challenge while 11 asthmatic subjects and all rhinitic subjects had a low-dose allergen challenge over four subsequent days. Induced sputum samples were obtained at 6 and 24 h after the conventional challenge and at days 2 and 4 of the low-dose challenge. RESULTS: In the asthmatic group, there was a weak correlation between wheal diameter induced by the concentration used for challenge and increase in eosinophils 6 h postconventional challenge (r = 0.372, P = 0.05), but no correlation was observed following the low-dose challenge. Rhinitic subjects showed a correlation between wheal diameter with the allergen dose used for bronchoprovocation and increase in eosinophils at day 2 of low dose (r = 0.608, P = 0.02). CONCLUSION: This study suggests that immediate immune responsiveness to allergen, assessed by the magnitude of the skin response, is a significant determinant of allergen-induced airway eosinophilia and can help to predict the airway inflammatory response.     

Airways of allergic rhinitics are 'primed' to repeated allergen inhalation challenge

The hypothesis that repeated exposure to a specific allergen will further increase bronchial responsiveness to that allergen is supported by indirect evidence. However, it has not been tested as intensely in the laboratory setting, and in some cases, conflicting results are presented. In order to test the hypothesis in the atopic subjects, allergen inhalation challenge tests were performed in 29 house dust mite (Dermatophagoides pternyssinus) sensitive subjects with allergic rhinitis. Nine subjects displayed early asthmatic responses (EARs) to the first challenge (Group 1). Twenty subjects with no significant airway response were submitted to the second challenge 24 h later. Thirteen subjects showed EARs (Group FI) and two of these showed late asthmatic responses (LARs)aswell. In Group II, there were significant changes between the first and second challenge in post-allergen early phase FEV₁, (88.1 ± 4.2 vs 71.7 ± 4.2%, baseline, P < 0.05) and in post-allergen late phase FEV₁, (93.1 ± 3.4 vs 86.6 ± 7.8. P < 0.05). After the second challenge. PD20 (provocative dose of methacholine required to produce a 20% fall in FEV¹) decreased significantly from the baseline values. When challenged separately with twofold dose of allergen, only three and one of the Group II showed EAR and LAR respectively. PD20 did not change significantly after this challenge. These results indicated that two repeated exposure to allergen dose, which is not enough to cause significant airway responses at a time, may provoke asthmatic airway responses in the subjects with allergic rhinitis and that this effect of priming is not attributed to the cumulative dose but to the consequent effect of repeated allergen exposure.     

Endotoxins and allergy: lessons from the murine model.

Exposure early in life to organic dusts containing immunomodulatory components such as endotoxins and immunizing components such as aeroallergens may greatly influence whether subsequent encounters with allergens lead rather to sensitization or unresponsiveness. We investigated the effects of endotoxin in the context of allergen-mediated immune responses in a murine model of allergen sensitization. Systemic sensitization with ovalbumin induced high serum levels of allergen-specific IgE, predominant Th2-type cytokine production, eosinophilic airway inflammation and in vivo airway hyperreactivity. Endotoxins were either applied systemically prior to sensitization, or via the airways prior to airway challenges, or by repeated inhalation during the first weeks of life prior to subsequent sensitization. Different effects of endotoxins on allergen-induced immune responses may be attributed to differences in dosing, route of application, time relationship with allergen sensitization and the concurrent exposure to endotoxin and allergen. The results of these studies may help to define the effects of endotoxin on allergen-mediated immune reactions and to further delineate the important interrelationships between environment and disease development. Finally, this may lead to new strategies in the prevention and treatment of allergic diseases.     

Neonatal exposure with LPS and/or allergen prevents experimental allergic airways disease: development of tolerance using environmental antigens

BACKGROUND: Studies show that children in rural environments develop less asthma and allergic rhinitis than their urban counterparts. This may be a result, in part, of neonatal exposure to environmental antigens such as LPS and/or early exposure to allergens. OBJECTIVE: This study examined the effects of neonatal allergen and/or LPS exposure on subsequent immune responses to allergen. METHODS: Newborn mice were exposed to LPS and/or ovalbumin. At age 6 weeks, these animals were sensitized and challenged with ovalbumin, and airway inflammation, hyperresponsiveness, and cytokine expression were assessed. RESULTS: Animals exposed to LPS in the neonatal period developed T cells expressing CD25 and IL-10 on sensitization and challenge. They demonstrated abrogation of airway hyperresponsiveness and significant decreases in IL-13 from bronchoalveolar lavage fluid and in specific IgE. IL-4-expressing spleen cells were also significantly decreased. Mice exposed in the neonatal period to ovalbumin demonstrated airway hyporesponsiveness after subsequent ovalbumin sensitization and challenge and did not produce specific IgE. In contrast, these animals showed increases in IFN-gamma. Animals exposed to both LPS and ovalbumin developed a response characterized by IL-10 and IFN-gamma-expressing T cells. CONCLUSION: This suggests that mucosal antigen exposure in the neonatal period results in inhibition of allergic responses to environmental allergens. Early LPS exposure directs mucosal responses toward tolerance, whereas ovalbumin exposure follows the T(H)1-type response on subsequent sensitization. CLINICAL IMPLICATIONS: This study suggests that prevention of airways allergy may be best achieved by appropriate exposure of the airway mucosa early in life to environmental antigens.     

Pro/Con debate: is occupational asthma induced by isocyanates an immunoglobulin E‐mediated disease?

Isocyanates, low‐molecular weight chemicals essential to polyurethane production, are one of the most common causes of occupational asthma, yet the mechanisms by which exposure leads to disease remain unclear. While isocyanate asthma closely mirrors other Type I Immune Hypersensitivity (Allergic) disorders, one important characteristic of hypersensitivity (‘allergen’‐specific IgE) is reportedly absent in a large portion of affected individuals. This variation from common environmental asthma (which typically is induced by high‐molecular weight allergens) is important for two reasons. (1) Allergen‐specific IgE is an important mediator of many of the symptoms of bronchial hyper‐reactivity in ‘allergic asthma’. Lack of allergen‐specific IgE in isocyanate hypersensitive individuals suggests differences in pathogenic mechanisms, with potentially unique targets for prevention and therapy. (2) Allergen‐specific IgE forms the basis of the most commonly used diagnostic tests for hypersensitivity (skin prick and RAST). Without allergen‐specific IgE, isocyanates may go unrecognized as the cause of asthma. In hypersensitive individuals, chronic exposure can lead to bronchial hyperreactivity that persists years after exposure ceases. Thus, the question of whether or not isocyanate asthma is an IgE‐mediated disease, has important implications for disease screening/surveillance, diagnosis, treatment and prevention. The present Pro/Con Debate, addresses contemporary, controversial issues regarding IgE in isocyanate asthma. Cite this as: A. V. Wisnewski and M. Jones, Clinical & Experimental Allergy, 2010 (40) 1155–1162.     

Exposure to endotoxin and allergen in early life and its effect on allergen sensitization in mice

BACKGROUND: Exposure to endotoxins, allergens, or both in early life might regulate the development of tolerance to allergens later in life. OBJECTIVE: We investigated whether continuous exposure of infant mice to aerosolized endotoxin, allergen, or both inhibits subsequent allergen-induced immune and inflammatory responses. METHODS: Infant BALB/c mice were pre-exposed to aerosolized endotoxin, ovalbumin (OVA), or both (3 times a week for the first 4 weeks of life) before systemic sensitization (days 1-14) and repeated airway challenge (days 28-30) with OVA. RESULTS: Compared with that seen in negative control animals, systemic sensitization and airway allergen challenges induced high serum levels of allergen-specific IgE (0.7 +/- 0.09 vs 0.02 +/- 0.01 OD units), predominant T(H)2-type cytokine production (IL-5 by splenic mononuclear cells in vitro, 1.2 +/- 0.2 vs 0.04 +/- 0.06 ng/mL), airway inflammation (bronchoalveolar lavage fluid leukocytes, 125 +/- 15 vs 64 +/- 7/microL; eosinophils, 28 +/- 5 vs 1 +/- 0/microL) and development of in vivo airway hyperreactivity (maximal enhanced pause, 11 +/- 1.9 vs 4 +/- 0.2). Pre-exposure with LPS before sensitization increased production of specific IgG2a (67 +/- 10 vs 32 +/- 5 U/mL) but failed to prevent T(H)2-mediated immune responses. Pre-exposure with OVA or with OVA plus LPS completely suppressed allergen sensitization, airway inflammation, and development of in vivo airway hyperreactivity; values were similar to those of negative control animals. Inhibition was due to allergen-specific T-cell anergy indicated by omitted allergen-specific T(H)2 and T(H)1 immune responses. In addition, combined exposure to endotoxin and allergen induced a general shift toward an unspecific T(H)1 immune response. CONCLUSION: Exposure with endotoxins before allergen sensitization is not able to induce unresponsiveness but might decrease the susceptibility for sensitization to a variety of common allergens.     

Repeatability of allergen-induced airway inflammation.

BACKGROUND: Allergen inhalation challenge is a useful clinical model to investigate the effects of asthma therapies on allergen-induced airway responses; however, the repeatability of allergen-induced airway inflammation is not known. OBJECTIVE: The purpose of this study was to investigate the repeatability of allergen-induced increases in sputum eosinophils. This information will allow the prediction of the number of subjects required in studies evaluating asthma therapies. METHODS: Seventeen subjects completed 2 allergen challenges using the same dose of allergen, at least 3 weeks apart. Allergen-induced airway responses were measured for 7 hours after challenge. Differential cell counts from induced sputum were determined the day before and 7 and 24 hours after challenge; methacholine PC20 was measured the day before and 24 hours after challenge. RESULTS: The intraclass correlation coefficient for maximum percent late fall in FEV1 was 0.32 and for the area of the late response was 0.61. The sample size predicted to be necessary to observe 50% attenuation of the maximum percent late fall in FEV1 and the late area under the curve with a power of 0.95 was 9 subjects. The intraclass correlation coefficient for percent of allergen-induced sputum eosinophils was 0.60 at 7 hours and 0.53 at 24 hours after challenge. With a randomized cross-over study design, the sample size predicted to be necessary to observe 50% attenuation of allergen-induced percent of eosinophils with a power of 0.95 was 5 subjects. CONCLUSION: Allergen inhalation challenge with measurements of sputum eosinophils is a noninvasive and reliable method for evaluating the anti-inflammatory effects of asthma therapies.