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Allergic bronchial asthma is a chronic inflammatory disorder of the airways characterized by a T helper 2 (TH2) cell triggered airway eosinophilia, development of airway hyperresponsiveness, mucus hyper secretion and structural changes of the airway wall summarized as airway remodeling. Current asthma therapy aims at controlling the inflammatory response in the airways by using corticosteroids in mild-moderate asthmatics. With increasing disease severity addition of further medication is required and includes long acting beta(2)-agonists or even immune suppressive drugs such as azathioprine, methotrexate or cyclophosphamide. Due to considerable side effects of these drugs especially underhigh dose treatment conditions controlling moderate-severe asthma represents an unmet medical need. Over the last 15 years mouse models of allergic asthma increased the knowledge about the pathophysiology of allergic asthma dramatically and led to several new therapeutic approaches such as the development of a monoclonal antibody against IgE. However, since TH2 cells seem to play a pivotal role in orchestrating the inflammatory response underlying asthma pathology these cells are predisposed as targets for therapeutic intervention. Thus, the present article further discusses several relevant patents and the current status of experimental approaches towards asthma therapy that aim at neutralizing TH2 cell effector functions, TH2 cell development, TH2 cell recruitment, and immunomodulation.

Chronic airway inflammation is the cornerstone on which bronchial asthma arises, and in turn, chronic inflammation arises from a complex interplay between environmental factors such as allergens and pathogens and immune cells as well as structural cells constituting the airway mucosa. Airway epithelial cells (AECs) are at the center of these processes. On the one hand, they represent the borderline separating the body from its environment in order to keep inner homeostasis. The airway epithelium forms a multi-tiered, self-cleaning barrier that involves an unstirred, discontinuous mucous layer, the dense and rigid mesh of the glycocalyx, and the cellular layer itself, consisting of multiple, densely interconnected cell types. On the other hand, the airway epithelium represents an immunologically highly active tissue once its barrier has been penetrated: AECs play a pivotal role in releasing protective immunoglobulin A. They express a broad spectrum of pattern recognition receptors, enabling them to react to environmental stressors that overcome the mucosal barrier. By releasing alarmins—proinflammatory and regulatory cytokines—AECs play an active role in the formation, strategic orientation, and control of the subsequent defense reaction. Consequently, the airway epithelium is of vital importance to chronic inflammatory diseases, such as asthma. [ABSTRACT FROM AUTHOR]

IL-17 cytokines are expressed by numerous cells (e.g., gamma delta (γδ) T, innate lymphoid (ILC), Th17, epithelial cells). They contribute to the elimination of bacteria through the induction of cytokines and chemokines which mediate the recruitment of inflammatory cells to the site of infection. However, IL-17-driven inflammation also likely promotes the progression of chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), lung cancer, cystic fibrosis, and asthma. In this review, we highlight the role of IL-17 cytokines in chronic lung diseases. [ABSTRACT FROM AUTHOR]

Background: The interleukin 17 receptor E (IL-17RE) is specific for the epithelial cytokine interleukin-17C (IL-17C). Asthma exacerbations are frequently caused by viral infections. Polyinosinic:polycytidylic acid (pIC) mimics viral infections through binding to pattern recognition receptors (e.g. TLR-3). We and others have shown that pIC induces the expression of IL-17C in airway epithelial cells. Using different mouse models, we aimed to investigate the function of IL-17RE in the development of experimental allergic asthma and acute exacerbation thereof.Methods: Wild-type (WT) and IL-17RE deficient (Il-17re-/-) mice were sensitized and challenged with OVA to induce allergic airway inflammation. pIC or PBS were applied intranasally when allergic airway inflammation had been established. Pulmonary expression of inflammatory mediators, numbers of inflammatory cells, and airway hyperresponsiveness (AHR) were analyzed.Results: Ablation of IL-17RE did not affect the development of OVA-induced allergic airway inflammation and AHR. pIC induced inflammation independent of IL-17RE in the absence of allergic airway inflammation. Treatment of mice with pIC exacerbated pulmonary inflammation in sensitized and OVA-challenged mice in an IL-17RE-dependent manner. The pIC-induced expression of cytokines (e.g. keratinocyte-derived chemokine (KC), granulocyte-colony stimulating factor (G-CSF)) and recruitment of neutrophils were decreased in Il-17re-/- mice. pIC-exacerbated AHR was partially decreased in Il-17re-/- mice.Conclusions: Our results indicate that IL-17RE mediates virus-triggered exacerbations but does not have a function in the development of allergic lung disease. [ABSTRACT FROM AUTHOR]

Background and Aims: Specific hyper-responsiveness towards an allergen and non-specific airway hyperreactivity both impair quality of life in patients with respiratory allergic diseases. We aimed to investigate cellular responses following specific and non-specific airway challenges locally and systemically in i) sensitized BALB/c mice challenged with grass pollen allergen Phl p 5, and in ii) grass pollen sensitized allergic rhinitis subjects undergoing specific airway challenge in the Vienna Challenge Chamber (VCC). Methods and Results: BALB/c mice (n = 20) were intraperitoneally immunized with grass pollen allergen Phl p 5 and afterwards aerosol challenged with either the specific allergen Phl p 5 (n = 10) or the non-specific antigen ovalbumin (OVA) (n = 10). A protocol for inducing allergic asthma as well as allergic rhinitis, according to the united airway concept, was used. Both groups of exposed mice showed significantly reduced physical activity after airway challenge. Specific airway challenge further resulted in goblet cell hyperplasia, enhanced mucous secretion, intrapulmonary leukocyte infiltration and lymphoid follicle formation, associated with significant expression of IL-4, IL-5 and IL-13 in splenocytes and also partially in lung tissue. Concerning circulating blood cell dynamics, we observed a significant drop of erythrocyte counts, hemoglobin and hematocrit levels in both mouse groups, challenged with allergen or OVA. A significant decrease in circulating erythrocytes and hematocrit levels after airway challenges with grass pollen allergen was also found in grass pollen sensitized human rhinitis subjects (n = 42) at the VCC. The effects on peripheral leukocyte counts in mice and humans however were opposed, possibly due to the different primary inflammation sites. Conclusion: Our data revealed that, besides significant leukocyte dynamics, particularly erythrocytes are involved in acute hypersensitivity reactions to respiratory allergens. A rapid recruitment of erythrocytes to the lungs to compensate for hypoxia is a possible explanation for these findings. [ABSTRACT FROM AUTHOR]

Th2 cells play a central role in the pathogenesis of allergic bronchial asthma, since each of their characteristic cytokines such as IL-4, IL-5, IL-9 and IL-13 contributes to hallmarks of this disease, including airway eosinophilia, increased mucus production, production of allergen-specific IgE and development of airway hyper-responsiveness. Therefore, these cells are predisposed as target cells for therapeutic intervention. Experimental approaches targeted Th2-type effector cytokines, Th2-cell recruitment and Th2-cell development. Another strategy uses the immunomodulatory potential of tolerance-inducing cytokines such as IL-10 or of cytokines such as IL-12, IL-18 and IFN-γ that are able to induce a counterbalancing Th1 immune response. [ABSTRACT FROM AUTHOR]

Over the last decade mouse models of experimental asthma proved to be a valuable tool for the investigation of mechanisms that underlie acute allergic airway inflammation and development of airway hyperresponsiveness, two of the hallmarks of human asthma. Nevertheless, these acute models fail to reflect the aspects of this chronic disease because they do not represent any signs of chronicity and airway remodelling as it is defined by subepithelial fibrosis, goblet cell hyperplasia and airway smooth muscle cell hypertrophy. Recent mouse models were successful in overcoming these limitations by using chronic allergen-challenges. These new models of chronic experimental asthma now proved as a novel tool to examine the complex interaction of infiltrating inflammatory cells and structural cells such as fibroblasts and smooth muscle cells that ultimately leads to airway remodelling and stable airflow limitation. Recent studies clearly demonstrated that T helper 2 (TH2) cells and their typical cytokines play a critical role not only in airway inflammation but also in the development of airway remodelling. Since the transcription factor GATA-3 is essential for TH2 cell development and the production of several TH2 type cytokines this intracellular molecule represents a new promising target for therapeutic intervention in asthma that might even effect airway remodelling. [ABSTRACT FROM AUTHOR]

Viral infection of the respiratory tract represents the major cause of acute asthma exacerbations. dsRNA is produced as an intermediate during replication of respiratory viruses and triggers immune responses via TLR3. This study aimed at clarifying the mechanisms underlying TLR3 triggered exacerbation of experimental allergic asthma. The TLR3 ligand poly(inosinic-cytidylic) acid was applied intranasally to mice with already established experimental allergic asthma. Airway inflammation, cytokine expression, mucus production, and airway reactivity was assessed in wild-type, IL-17A, or IL-23pI9-deficient, and in NK cell-depleted mice. Local application of poly(inosinic-cytidylic) acid exacerbated experimental allergic asthma in mice as characterized by enhanced release of proinflammatory cytokines, aggravated airway inflammation, and increased mucus production together with pronounced airway hyperresponsiveness. This was further associated with augmented production of IL-17 by Thl7 cells and NK cells. Whereas experimental exacerbation could be induced in IL-23pl9-defieient mice lacking mature, proinflammatory Thl7 cells, this was not possible in mice lacking IL-17A or in NK cell-depleted animals. These experiments indicate a central role for IL-17 derived from NK cells but not from Thl7 cells in the pathogenesis of virus-triggered exacerbation of experimental asthma. [ABSTRACT FROM AUTHOR]