Human Allergic Asthma Research Articles

Activity of the cyclooxygenase 2-prostaglandin-E prostanoid receptor pathway in mice exposed to house dust mite aeroallergens, and impact of exogenous prostaglandin E2

BackgroundProstaglandin E2 (PGE2), experimentally administered to asthma patients or assayed in murine models, improves allergen-driven airway inflammation. The mechanisms are unknown, but fluctuations of the endogenous cyclooxygenase (COX)-2/prostaglandin/E prostanoid (EP) receptor pathway activity likely contribute to the clinical outcome. We analyzed the activity of the pathway in mice sensitized to aeroallergens, and then studied its modulation under exogenous PGE2.MethodsMice were exposed to house dust mite (HDM) aeroallergens, a model that enable us to mimic the development of allergic asthma in humans, and were then treated with either subcutaneous PGE2 or the selective EP1/3 receptor agonist sulprostone. Simultaneously with airway responsiveness and inflammation, lung COX-2 and EP receptor mRNA expression were assessed. Levels of PGE2, PGI2, PGD2 were also determined in bronchoalveolar lavage fluid.ResultsHDM-induced airway hyperreactivity and inflammation were accompanied by increased COX-2 mRNA production. In parallel, airway PGE2 and PGI2, but not PGD2, were upregulated, and the EP2 receptor showed overexpression. Subcutaneous PGE2 attenuated aeroallergen-driven airway eosinophilic inflammation and reduced endogenous PGE2 and PGI2 production. Sulprostone had neither an effect on airway responsiveness or inflammation nor diminished allergen-induced COX-2 and PGE2 overexpression. Finally, lung EP2 receptor levels remained high in mice treated with PGE2, but not in those treated with sulprostone.ConclusionThe lung COX-2/PGE2/EP2 receptor pathway is upregulated in HDM-exposed mice, possibly as an effort to attenuate allergen-induced airway inflammation. Exogenous PGE2 downregulates its endogenous counterpart but maintains EP2 overexpression, a phenomenon that might be required for administered PGE2 to exert its protective effect.

Impaired IL-10–dependent Induction of Tolerogenic Dendritic Cells by CD4+CD25hiCD127lo/−Natural Regulatory T Cells in Human Allergic Asthma

Tolerogenic dendritic cells and natural regulatory T cells have been implicated in the process of infectious tolerance in human allergic asthma. However, the significance of the influence of natural regulatory T cells on tolerogenic dendritic cells in the disease has not been investigated. We aimed to characterize the mechanism of induction of the tolerogenic phenotype in circulating blood dendritic cells by allergic asthmatic natural regulatory T cells. The study was performed in a cohort of 21 subjects with allergic asthma, 21 healthy control subjects, and 21 subjects with nonallergic asthma. We cultured blood dendritic cells with natural regulatory T cells to study the induction of tolerogenic dendritic cells. Flow cytometry and proliferation assays were employed to analyze phenotype and function of dendritic cells as well as IL-10 production from natural regulatory T cells. Dendritic cells cultured with natural regulatory T cells up-regulated IL-10, down-regulated costimulatory molecules, and stimulated the proliferation of CD4(+)CD25(-) effector T cells less potently. Allergic asthmatic natural regulatory T cells were significantly less efficient in inducing this tolerogenic phenotype of dendritic cells compared with healthy control and nonallergic asthmatic counterparts. Furthermore, this defective function of natural regulatory T cells was associated with their decreased IL-10 expression, disease severity, and could be reversed by oral corticosteroid therapy. These results provided the first evidences of impaired induction of tolerogenic dendritic cells mediated by natural regulatory T cells in human allergic asthma.

Inverse relationship between Sec14l3 mRNA/protein expression and allergic airway inflammation

Bronchial asthma is an inflammatory disease of the airways. The Sec14l3 gene, encoding a 45-kDa secretory protein, is specifically expressed in airway epithelium. Here, we report on the kinetics of Sec14l3 expression following allergic inflammation of the lung. Brown Norway rats were sensitized by intraperitoneal injection of ovalbumin, followed by challenge with aerosolized ovalbumin after a 3-week interval. This animal model showed many features similar to human allergic asthma: an increase in inflammatory cells such as eosinophils, lymphocytes and neutrophils in bronchoalveolar lavage (BAL) fluid and histopathological alteration of lung tissue, exhibiting infiltration of these inflammatory cells and degeneration and necrosis of alveolar epithelium. These parameters reached their maximal level 24 h after allergen challenge. In contrast, quantitative polymerase chain reaction analyses demonstrated a rapid and significant reduction of Sec14l3 mRNA in lung tissue and maximum reduction (to 1.4% of the control) was observed at 24 h. Pretreatment with dexamethasone significantly suppressed both the Sec14I3 mRNA reduction and all of the inflammatory changes. The 45-kDa secretory protein was identified in the supernatant of BAL fluids. Two-dimensional gel images of the supernatant proteome also revealed down-regulation of the protein following inflammation (to approximately 30% of the control at 24 h). Thus, Sec14l3 expression is highly and inversely associated with the progression of airway inflammation. Sec14l3 mRNA and protein may function in the homeostasis of airway epithelial cells under normal conditions.

Human Serum IgE Reacts with a Metarhizium anisopliae Fungal Catalase

Background: Previous studies have demonstrated that Metarhizium anisopliae extract can induce responses characteristic of human allergic asthma in a mouse model. The study objectives were (1) to identify and characterize the M. anisopliae mycelia extract (MYC) proteins that are recognized by mouse serum IgE, (2) to determine if human serum IgE reacts with these proteins, and (3) to determine if these IgE-reactive proteins are found in other fungi. Methods: Asthmatic human serum IgE, M. anisopliae crude antigen (MACA) immunized mouse serum IgE, and anti-catalase antibodies were used to probe one- and two-dimensional gel electrophoresis blots of MYC. Results: Mass spectrometry analysis identified catalase as a mouse IgE-reactive protein. This identification was confirmed by assaying catalase activity in the extract and extract immunoblots probed with anti-catalase antibody. Six adult asthmatic sera contained IgE, but not IgG, that was reactive with mycelia extract proteins. A similar protein profile was seen when blots were probed with either mouse anti-MACA IgE or anti-bovine liver catalase antibodies. Furthermore, these mouse anti-MACA and anti-catalase antibodies were cross-reactive with other mold extracts (skin prick testing mix) and Aspergillus niger catalase. Conclusions: Some human asthmatics have developed IgE that reacts with an M. anisopliae catalase, most likely due to cross-reactivity (minimal IgG development). The cross-reactivity among fungal catalases suggests that IgE-reactive catalase might be useful for exposure assessment. Additionally, the similarity of protein profiles visualized with both human and mouse serum IgE suggests that allergy hazard identification can be facilitated using a mouse model.

Animal models of airway inflammation and airway smooth muscle remodelling in asthma

Asthma is a complex disease that involves chronic inflammation and subsequent decline in airway function. The widespread use of animal models has greatly contributed to our understanding of the cellular and molecular pathways underlying human allergic asthma. Animal models of allergic asthma include smaller animal models which offer ‘ease of use’ and availability of reagents, and larger animal models that may be used to address aspects of allergic airways disease not possible in humans or smaller animal models. This review examines the application and suitability of various animal models for studying mechanisms of airway inflammation and tissue remodelling in allergic asthma, with a specific focus on airway smooth muscle.

Differential allergy responses to Metarhizium anisopliae fungal component extracts in BALB/c mice

Intratracheal aspiration (IA) exposure to Metarhizium anisopliae crude antigen (MACA), which is composed of equal protein amounts of mycelium (MYC), conidia (CON) and inducible proteases/chitinases (IND) extracts/filtrates, has resulted in responses characteristic of human allergic asthma in mice. The study objective was to evaluate the potential of each component extract to induce allergic/asthma-like responses observed in this mouse model. BALB/c mice received 4 IA exposures to MACA, CON, MYC, IND, or bovine serum albumin (BSA; negative control) or appropriate vehicle control or inflammatory control over a 4-wk period. Mice were assessed by whole-body plethysmography for immediate airway responses and airway hyperresponsiveness to methacholine (Mch) challenge (PenH). Serum and bronchoalveolar lavage fluid (BALF) were collected 3 d after the final exposure. Additionally, BALF neurotrophin levels and extract protease and chitinase activity levels were evaluated. Western blot analysis showed that each component contained different IgE-reactive proteins. All fungal extract exposures resulted in elevated BALF total and differential cell counts, IgE and IgA and total serum IgE compared to HBSS and BSA controls. MYC-exposed mice had the highest responses except for neutrophil influx, which was highest in MACA and IND exposures. However, the MYC-exposed mice had significantly lower PenH values compared to other treatments. By comparison IND and MACA induced significantly higher PenH values. Additionally, IND had substantially higher protease activity levels but induced the lowest neurotrophin levels compared to the other fungal exposures. In this allergic asthma model extract chitinase activity was not associated with allergic responses. In summary, multiple exposures to any of the M. anisopliae component extracts induced allergic/asthma-like responses in BALB/c mice but the response magnitude was different for each component and each appears to contain unique IgE-reactive proteins. Therefore, hazard identification and/or risk assessment for molds must test both mycelia and conidia.

Selective deregulation in chemokine signaling pathways of CD4+CD25hiCD127lo/− regulatory T cells in human allergic asthma

CD4+CD25(hi)CD127(lo)/(-) regulatory T cells have been suggested to be critical regulators of inflammatory processes in allergic asthma. Recent studies reported a selective decrease in the frequency of regulatory T cells in the bronchoalveolar lavage fluid of allergic asthmatic (AA) subjects, prompting the possibility of defective recruitment of these cells to the airway in response to chemokines produced during asthmatic inflammation. This study aimed to characterize the chemotactic profile of circulating regulatory T cells in AA subjects in response to chemokines abundantly produced in airway inflammation, such as CCL1, CCL17, and CCL22. The study was performed in a cohort of 26 AA, 16 healthy control, and 16 non-AA subjects. We used chemotaxis assays to evaluate cell migration, flow cytometry to examine chemokine receptor expression, and phospho-ELISA to study consequent signaling pathways in regulatory T cells. Regulatory T cells, but not CD4+CD25(-)T cells, from AA subjects showed decreased chemotactic responses, specifically to CCL1, in comparison with their healthy control and non-AA counterparts. Decreased CCL1-mediated chemotaxis in AA regulatory T cells was associated with decreased phosphorylation of protein kinase B (AKT), a protein involved in chemokine intracellular signaling. Furthermore, the decreased chemotactic response to CCL1 in AA regulatory T cells significantly correlated with asthma severity and decreased pulmonary function in AA subjects. These results provide the first evidence of dysfunction in the chemokine signaling pathway in AA regulatory T cells.

OR.6. Selective Deregulation in Chemokine Signaling Pathways of CD4+CD25hiCD127lo/-Regulatory T Cells in Human Allergic Asthma

OR.6. Selective Deregulation in Chemokine Signaling Pathways of CD4+CD25hiCD127lo/-Regulatory T Cells in Human Allergic Asthma

FcγRIV is a mouse IgE receptor that resembles macrophage FcεRI in humans and promotes IgE-induced lung inflammation

FcgammaRIV is a recently identified mouse activating receptor for IgG2a and IgG2b that is expressed on monocytes, macrophages, and neutrophils; herein it is referred to as mFcgammaRIV. Although little is known about mFcgammaRIV, it has been proposed to be the mouse homolog of human FcgammaRIIIA (hFcgammaRIIIA) because of high sequence homology. Our work, however, has revealed what we believe to be new properties of mFcgammaRIV that endow this receptor with a previously unsuspected biological significance; we have shown that it is a low-affinity IgE receptor for all IgE allotypes. Although mFcgammaRIV functioned as a high-affinity IgG receptor, mFcgammaRIV-bound monomeric IgGs were readily displaced by IgE immune complexes. Engagement of mFcgammaRIV by IgE immune complexes induced bronchoalveolar and peritoneal macrophages to secrete cytokines, suggesting that mFcgammaRIV may be an equivalent of human FceRI(alphagamma), which is expressed by macrophages and neutrophils and especially in atopic individuals, rather than an equivalent of hFcgammaRIIIA, which has no affinity for IgE. Using mice lacking 3 FcgammaRs and 2 FceRs and expressing mFcgammaRIV only, we further demonstrated that mFcgammaRIV promotes IgE-induced lung inflammation. These data lead us to propose a mouse model of IgE-induced lung inflammation in which cooperation exists between mast cells and mFcgammaRIV-expressing lung cells. We therefore suggest that a similar cooperation may occur between mast cells and hFceRI-expressing lung cells in human allergic asthma.

XCL1 Enhances Regulatory Activities of CD4+CD25highCD127low/− T Cells in Human Allergic Asthma

Chemokine-mediated recruitment of regulatory cell subsets to the airway during inflammation and enhancement of their activities are potential strategies for therapeutic development in allergic asthma (AA). In this study, we aim to explore the role of XCL1, a chemokine associated with immune suppression and allergy, on CD4(+)CD25(high)CD127(low/-) regulatory T cell (Treg) function in AA. Flow cytometry and PCR analysis showed a reduction in XCL1 and XCR1 expression in AA Treg compared with healthy control and nonallergic asthmatic counterparts. This reduction in XCL1 expression was associated with the suboptimal regulatory function of Treg in AA. Interestingly, incubation with recombinant human XCL1 significantly increased Treg-mediated suppression and cytotoxicity by up-regulating expression of XCL1 and chief effector molecules of Treg function. Altogether, these results suggest an association between dysregulated XCL1 expression and reduced Treg activities in AA, as well as a potential role of XCL1 in reversing defective Treg function in the disease.

IL-2 Receptor β-Chain Signaling Controls Immunosuppressive CD4+ T Cells in the Draining Lymph Nodes and Lung during Allergic Airway Inflammation In Vivo

IL-2 influences both survival and differentiation of CD4(+) T effector and regulatory T cells. We studied the effect of i.n. administration of Abs against the alpha- and the beta-chains of the IL-2R in a murine model of allergic asthma. Blockade of the beta- but not the alpha-chain of the IL-2R after allergen challenge led to a significant reduction of airway hyperresponsiveness. Although both treatments led to reduction of lung inflammation, IL-2 signaling, STAT-5 phosphorylation, and Th2-type cytokine production (IL-4 and IL-5) by lung T cells, IL-13 production and CD4(+) T cell survival were solely inhibited by the blockade of the IL-2R beta-chain. Moreover, local blockade of the common IL-2R/IL-15R beta-chain reduced NK cell number and IL-2 production by lung CD4(+)CD25(+) and CD4(+)CD25(-) T cells while inducing IL-10- and TGF-beta-producing CD4(+) T cells in the lung. This cytokine milieu was associated with reduced CD4(+) T cell proliferation in the draining lymph nodes. Thus, local blockade of the beta-chain of the IL-2R restored an immunosuppressive cytokine milieu in the lung that ameliorated both inflammation and airway hyperresponsiveness in experimental allergic asthma. These findings provide novel insights into the functional role of IL-2 signaling in experimental asthma and suggest that blockade of the IL-2R beta-chain might be useful for therapy of allergic asthma in humans.

Cockroach Allergen Induced Asthma in Outbred Mice

Our lab has previously demonstrated the ability of German cockroach allergens (CRA) to induce allergic‐type airways inflammation in BALB/c mice. This model resembles human allergic asthma in its histology, symptomatology and airways hyperreactivity. We reproduced this model in outbred (ICR) mice to extend our observations and establish a more applicable model to the extremely outbred human population. Mice were given 4.75ug, 2.4ug and 2.4ug of CRA intratracheally on days 0, 14, and 21. Airways hyperresponsiveness (AHR) and cell content of bronchoalveolar lavage fluid was measured 24 hours post final challenge and the results compared to BALB/c mice.Because of the encouraging data this model has produced, and the greater applicability of its genetically diverse background, we believe outbred animal experiments are highly appropriate in simulating human disease.

Inhibition of airway eosinophilia and pulmonary pathology in a mouse model of allergic asthma by the live vaccine strain of Francisella tularensis

It has been suggested that exposure to certain microbes and their products, particularly during neonatal and early childhood periods, may shift the immune response towards a T-helper cell (Th) 1 phenotype and thereby prevent the development of and/or alleviate the clinical symptoms of allergic airway diseases. We evaluated the ability of the live vaccine strain (LVS) of Francisella tularensis to suppress airway eosinophilia and pulmonary pathology in a murine model of allergic airway disease. C57BL/6 mice were sensitized by intraperitoneal injection of ovalbumin (OVA) on days 1 and 14, and challenged intranasally (i.n.) with OVA on day 21 or thereafter. Some sensitized mice were i.n. treated with live LVS or its cell-free sonicate extract (CFSE) before i.n. OVA challenge. Bronchoalveolar lavage fluid, regional lymph node cells, lung tissues and serum samples were collected 3-7 days after the i.n. challenge. Intranasal and, to a lesser degree, intradermal immunization of OVA-sensitized mice with LVS suppressed the development of airway eosinophilia and associated pulmonary pathology induced by i.n. OVA challenge. Moreover, CFSE prepared from LVS showed a similar inhibitory effect whereas neither LPS nor DNA purified from F. tularensis LVS had such an effect. The inhibition was associated with the reduction in mRNA expression and protein levels of Th2 cytokines IL-5 and IL-13 in the lungs and the enhanced production of OVA-induced IFN-gamma by local draining lymph node cells, but not with the serum levels of OVA-specific IgG1 or IgE. F. tularensis LVS is capable of suppressing allergic airway inflammation probably through a Th1-mediated suppression of an ongoing Th2 response mechanism, and raises the possibility of exploring LVS and its components as potential therapeutic modalities for human allergic asthma.

Immune response to allergens in sheep sensitized to house dust mite

BackgroundHouse dust mite (HDM) allergens are a major cause of allergic asthma. Most studies using animal models of allergic asthma have used rodents sensitized with the 'un-natural' allergen ovalbumin. It has only recently been recognized that the use of animal models based on HDM provide a more relevant insight into the allergen-induced mechanisms that underpin human allergic disease. We have previously described a sheep model of human allergic asthma that uses Dermatophagoides pteronyssinus HDM. The present study extends our understanding of the immune effects of HDM and the allergens Der p 1 and Der p 2 in the sheep model of asthma.MethodsPeripheral blood sera from non-sensitized (control) sheep and sheep sensitized to HDM was collected to determine immunoglobulin (Ig) reactivities to HDM, Der p 1 and Der p 2 by ELISA. Bronchoalveolar lavage (BAL) fluid collected following allergen challenge was also assessed for the presence of HDM-specific antibodies. To examine the cellular immune response to HDM allergens, T cell proliferation and cutaneous responses were assessed in sensitized and control sheep.ResultsStrong HDM- and Der p 1-specific IgE, IgG1, IgG2 and IgA serum responses were observed in sensitized sheep, while detectable levels of HDM-specific IgG1 and IgA were seen in BAL fluid of allergen-challenged lungs. In contrast, minimal antibody reactivity was observed to Der p 2. Marked T cell proliferation and late phase cutaneous responses, accompanied by the recruitment of eosinophils, indicates the induction of a cellular and delayed-type hypersensitivity (DTH) type II response by HDM and Der p 1 allergen, but not Der p 2.ConclusionThis work characterizes the humoral and cellular immune effects of HDM extract and its major constituent allergens in sheep sensitized to HDM. The effects of allergen in HDM-sensitized sheep were detectable both locally and systemically, and probably mediated via enzymatic and immune actions of the major HDM allergen Der p 1. This study extends our understanding of the actions of this important allergen relevant to human allergic asthma and its effects in sheep experimentally sensitized to HDM allergens.

Safety of segmental allergen challenge in human allergic asthma

Segmental allergen challenge is widely used to study mechanisms of human allergic asthma. Despite the relatively large dissemination, limited information is available about the safety of this method. Observational, retrospective study to report the adverse events of segmental allergen challenge in a large group of volunteers with asthma. In total, 78 cases from several studies performed between 1994 and 2007 were pooled for this analysis. Volunteers underwent allergen challenge using either a fixed dose of allergen (7 cases) or an individually standardized allergen dose defined by an inhaled allergen test before the challenge (71 cases). A subgroup of 13 volunteers underwent repeated challenges, with more than 6 months between the challenges. With a fixed dose instilled during bronchoscopy, 43% of the participants developed wheezing and coughing, requiring 2-6 puffs of a ss(2)-agonist after segmental allergen challenge. In volunteers with individually standardized doses, a ss(2)-agonist was required in only 19% of the cases. No severe adverse events occurred in all cases studied. Volunteers who underwent repeated challenges did not develop more adverse events than those who underwent 1 challenge. Segmental allergen challenge is a safe tool to study the mechanisms of human allergic asthma, even when repeated challenges are performed in the same patient. It is associated with only a few, tolerable adverse events, especially when the dose of allergen is standardized individually.

Roles of integrin activation in eosinophil function and the eosinophilic inflammation of asthma

Eosinophilic inflammation is a characteristic feature of asthma. Integrins are highly versatile cellular receptors that regulate extravasation of eosinophils from the postcapillary segment of the bronchial circulation to the airway wall and airspace. Such movement into the asthmatic lung is described as a sequential, multistep paradigm, whereby integrins on circulating eosinophils become activated, eosinophils tether in flow and roll on bronchial endothelial cells, integrins on rolling eosinophils become further activated as a result of exposure to cytokines, eosinophils arrest firmly to adhesive ligands on activated endothelium, and eosinophils transmigrate to the airway in response to chemoattractants. Eosinophils express seven integrin heterodimeric adhesion molecules: alpha 4 beta 1 (CD49d/29), alpha 6 beta 1 (CD49f/29), alpha M beta 2 (CD11b/18), alpha L beta 2 (CD11a/18), alpha X beta 2 (CD11c/18), alpha D beta2 (CD11d/18), and alpha 4 beta 7 (CD49d/beta 7). The role of these integrins in eosinophil recruitment has been elucidated by major advances in the understanding of integrin structure, integrin function, and modulators of integrins. Such findings have been facilitated by cellular experiments of eosinophils in vitro, studies of allergic asthma in humans and animal models in vivo, and crystal structures of integrins. Here, we elaborate on how integrins cooperate to mediate eosinophil movement to the asthmatic airway. Antagonists that target integrins represent potentially promising therapies in the treatment of asthma.

The Tick Salivary Protein, Salp15, Inhibits the Development of Experimental Asthma

Activation of Th2 CD4(+) T cells is necessary and sufficient to elicit allergic airway disease, a mouse model with many features of human allergic asthma. Effectively controlling the activities of these cells could be a panacea for asthma therapy. Blood-feeding parasites have devised remarkable strategies to effectively evade the immune response. For example, ticks such as Ixodes scapularis, which must remain on the host for up to 7 days to feed to repletion, secrete immunosuppressive proteins. Included among these proteins is the 15-kDa salivary protein Salp15, which inhibits T cell activation and IL-2 production. Our objective for these studies was to evaluate the T cell inhibitory properties of Salp15 in a mouse model of allergic asthma. BALB/cJ mice were Ag sensitized by i.p. injection of OVA in aluminum hydroxide, with or without 50 mug of Salp15, on days 0 and 7. All mice were challenged with aerosolized OVA on days 14-16 and were studied on day 18. Compared with control mice sensitized with Ag, mice sensitized with Ag and Salp15 displayed significantly reduced airway hyperresponsiveness, eosinophilia, Ag-specific IgG1 and IgE, mucus cell metaplasia, and Th2 cytokine secretion in vivo and by CD4(+) T cells restimulated with Ag in vitro. Our results demonstrate that Salp15 can effectively prevent the generation of a Th2 immune response and the development of experimental asthma. These studies, and those of others, support the notion that a lack of ectoparasitism may contribute to the increasing prevalence of allergic asthma.

Pollen‐induced airway inflammation, hyper‐responsiveness and apoptosis in a murine model of allergy

Previous studies indicate that murine models are useful tools for studying the allergic diseases, including certain aspects of bronchial asthma such as cellular tissue inflammation and pulmonary function. To develop an experimental model of allergic lung inflammation based on a relevant human allergen, olive pollen, and to establish the immunological, cellular and functional airway features of the allergic response in this model. Induction of systemic allergic response was achieved by the subcutaneous administration of Olea europaea extract in BALB/c mice. Olea-specific Igs (IgG1, IgG2a and IgE) and cytokines from splenocyte cultures IL-4, IL-5 IL-10, IL-13 and IFN-gamma were measured. Allergic airway response was generated by transnasal instillation of the allergens. Airway responsiveness was monitored by non-invasive methacholine inhalation challenge. Lungs were paraffin embedded and histologically analysed. Apoptosis was studied by the TUNEL technique in the lung tissue and through cell cycle analysis by flow cytometry in splenocytes. Our results demonstrate that Olea-sensitized mice develop a specific allergic antibody (IgG1 and IgE) and cytokine (IL-4, IL-5, IL-10 and IL-13) response. After transnasal Olea instillation, they show inflammatory infiltration of lung tissue, mucus secretion and non-specific hyper-responsiveness in the airway. Concomitantly, differences in the rate of apoptosis are observed in the lung cells as well as a significant reduction of spontaneous apoptosis in the splenocytes of allergic mice. We present a novel animal model of olive pollen-allergic disease. This model presents traits associated with human allergic asthma and could be an interesting tool in the study of underlying molecular mechanisms and in exploring the therapeutic approaches to this disease.

Fungal airborne allergen challenge: mimicking environmental exposure

Allergic asthma afflicts 16 million adults and nine million children in the United States with an approximated annual cost to the economy of $14 billion. Current animal models of human allergic asthma do not accurately mimic natural environmental exposure, limiting our ability to clarify disease mechanisms responsible for acute and chronic pathogenesis. To this aim, we have developed an airborne delivery method for the clinically-relevant allergen Aspergillus fumigatus. Like the current liquid delivery system, the airborne method exhibits many of the hallmark signs of acute allergic asthma: methacholine-induced airway hyperresponsiveness, bronchial eosinophilia, lymphocyte infiltration into the lungs, and increased mucus secretion. In addition, a significant improvement in pulmonary dispersion of the fungus indicates that airborne delivery incorporates the contribution of the small airways in the disease model much as it would be in the clinical setting. This may be of particular benefit in studying chronic disease symptoms such as goblet cell hyperplasia and fibrosis.

Asthma: a comparison of animal models using stereological methods

Asthma is a worldwide health problem that affects 300 million people, as estimated by the World Health Organization. A key question in light of this statistic is: “what is the most appropriate laboratory animal model for human asthma?” The present authors used stereological methods to assess airways in adults and during post-natal development, and their response to inhaled allergens to compare rodents and nonhuman primates to responses in humans. An epithelial–mesenchymal trophic unit was defined in which all of the compartments interact with each other. Asthma manifests itself by altering not only the epithelial compartment but also other compartments ( e.g. interstitial, vascular, immunological and nervous). All of these compartments show significant alteration in an airway generation-specific manner in rhesus monkeys but are limited to the proximal airways in mice. The rhesus monkey model shares many of the key features of human allergic asthma including the following: 1) allergen-specific immunoglobulin (Ig)E and skin-test positivity; 2) eosinophils and IgE+ cells in airways; 3) a T-helper type 2 cytokine profile in airways; 4) mucus cell hyperplasia; 5) subepithelial fibrosis; 6) basement membrane thickening; and 7) persistent baseline hyperreactivity to histamine or methacholine. In conclusion, the unique responses to inhaled allergens shown in rhesus monkeys make it the most appropriate animal model of human asthma.