Murine asthma models suggest that failure of immune tolerance rather than a defective T helper cell type 1 (Th1) immunity underlies the immune biology of Th2-driven allergen-induced airway disease. Intriguingly, prolonged exposures can result in a full waning of inflammation. The mechanisms underlying this observation are not understood. We hypothesized that the fading of inflammation is the result of regulatory processes, characterized by altered dendritic cell (DC)-T cell interactions. First, we implemented a model in which mice developed Th2-driven airway disease. When we subjected these mice to prolonged antigen ovalbumin (OVA) exposures (8 wk), all inflammation disappeared. Re-immunization and re-challenge showed an inability to mount Th2-skewed immune responses, with absence of airway eosinophils, IgE, and Th2 cytokines. Besides specific immune tolerance, bystander protection was observed. A decrease in CD4 ϩ CD25 ϩ Foxp3 ϩ T-regulatory cells, PD-1, and IL-10 expression was discerned as compared with acute inflammation. In addition, suppression of ICOS and CD28 was found, along with inhibited DC maturation. This process of disease inhibition surprisingly had a long-lasting memory and was not caused by endotoxin signaling through TLR-4. In summary, our results indicate that the disappearance of Th2-driven airway disease upon persistent antigen exposure is associated with the induction of immune tolerance. The tolerant state is antigen-dependent, and extends to bystander antigens. Moreover, this tolerance is characterized by an altered DC-T cell communication and is long-lasting. Our data further suggest that the mechanism of the disease inhibition after allergic airway inflammation differs from the anti-inflammatory mechanisms observed during acute eosinophilic airway inflammation.

Background: The interactions between airway responsiveness, structural remodelling and inflammation in allergic asthma remain poorly understood. Prolonged challenge with inhaled allergen is necessary to replicate many of the features of airway wall remodelling in mice. In both mice and humans, genetic differences can have a profound influence on allergy, inflammation, airway responsiveness and structural changes. Methods: The aim of this study was to provide a comparative analysis of allergen-induced airway changes in sensitized BALB/c and C57BL/6 mice that were exposed to inhaled allergen for 2 (‘acute’), 6 or 9 weeks (‘chronic’). Inflammation, remodelling and responsiveness were analyzed. Results: Both strains developed a Th-2-driven airway inflammation with allergen-specific IgE, airway eosinophilia and goblet cell hyperplasia upon 2 weeks of allergen inhalation. This was accompanied by a significant increase in airway smooth muscle mass and hyperresponsiveness in BALB/c but not in C57BL/6 mice. However, airway eosinophilia was more pronounced in the C57BL/6 strain. Chronic allergen exposure (6 or 9 weeks) resulted in an increase in airway smooth muscle mass as well as subepithelial collagen and fibronectin deposition in both strains. The emergence of these structural changes paralleled the disappearance of inflammation in both C57BL/6 and BALB/c mice and loss of hyperresponsiveness in the BALB/c strain. TGF-β₁ was accordingly elevated in both strains. Conclusion: Airway inflammation, remodelling and hyperresponsiveness are closely intertwined processes. Genetic background influences several aspects of the acute allergic phenotype. Chronic allergen exposure induces a marked airway remodelling that parallels a decreased inflammation, which was largely comparable between the two strains.

Cigarette smoke enhances acute allergic inflammation and delays, but does not abrogate the development of tolerance due to prolonged challenge with inhaled antigen in experimental asthma.

Recent investigations have highlighted that endogenous anti‐inflammatory mediators and immune regulating mechanisms are important for the resolution of inflammatory processes. A disruption of these mechanisms can be causally related not only to the initiation of unnecessary inflammation, but also to the persistence of several chronic inflammatory diseases. In asthma, chronic Th‐2 driven eosinophilic inflammation of the airways is one of the central abnormalities. To date, elucidating the role of the different pro‐inflammatory mediators involved in orchestrating the inflammatory processes in asthma has been the subject of intense research in both humans and animal models. However, the counter‐regulatory mechanisms that co‐determine the outcome in the contest of resolution vs persistence of the eosinophilic airway inflammation remain poorly understood. These are currently being investigated in animal models of chronic asthma. Elucidating these mechanisms is of relevance, since it can give rise to a new therapeutic approach in the treatment of chronic airway inflammation in asthmatics. This novel concept of treatment involves the stimulation of endogenous anti‐inflammatory pathways, rather than solely antagonising the various pro‐inflammatory mediators. Here, we review and discuss the current knowledge about these endogenous anti‐inflammatory mediators in clinical and experimental asthma.

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