Published ahead of print on January 11, 2007, doi:10.1165/rcmb.2006-0385OC Am. J. Respir. Cell Mol. Biol., Volume 36, Number 5, May 2007, 573-584 A more recent version of this article appeared on May 1, 2007
Submitted on October 13, 2006 Prolonged Inhaled Allergen Exposure Can Induce Persistent ToleranceChris L Van Hove1,1 Faculty of Medicine and Ghent University Hospital, Department of Respiratory Diseases, Ghent University, Ghent, Belgium * To whom correspondence should be addressed. E-mail: kurt.tournoy{at}UGent.be.
ABSTRACT Murine asthma models suggest that failure of immune tolerance rather than a defective Th-1 immunity underlies the immune-biology of Th-2 driven allergen induced airway disease. Intriguingly, prolonged exposures 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 Th-2 driven airway disease. When we subjected these mice to prolonged antigen ovalbumin (OVA) exposures (8 weeks), all inflammation disappeared. Re-immunization and re-challenge showed an inability to mount Th-2 skewed immune responses, with absence of airway eosinophils, IgE and Th-2 cytokines. Besides specific immune tolerance, bystander protection was observed. A decrease in CD4+CD25+Foxp3+ T-regulatory cells, PD-1 and IL-10 expression was discerned as compared to 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 signalling through TLR-4. In summary, our results indicate that the disappearance of Th-2 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 following allergic airway inflammation differs from the anti-inflammatory mechanisms observed during acute eosinophilic airway inflammation.
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