Prolonged inhaled allergen exposure can induce persistent tolerance.
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+CD25+Foxp3+ 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.
Van Hove
Chris L
CL
Department of Respiratory Diseases, Faculty of Medicine, Ghent University and Ghent University Hospital 7K12 I.E., De Pintelaan 185, 9000 Ghent, Belgium.
Maes
Tania
T
Joos
Guy F
GF
Tournoy
Kurt G
KG
D000485:Allergens / Q000008:administration & dosage*; D000818:Animals; D000941:Antigens / Q000008:administration & dosage; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D024201:Bystander Effect / Q000276:immunology; D002450:Cell Communication; D003713:Dendritic Cells / Q000166:cytology; D004804:Eosinophils / Q000276:immunology; D005434:Flow Cytometry; D007108:Immune Tolerance / Q000276:immunology*; D007073:Immunoglobulin E / Q000097:blood; D007156:Immunologic Memory; D007249:Inflammation; D019570:Inhalation Exposure; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D012137:Respiratory System / Q000276:immunology / Q000473:pathology; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000378:metabolism
D000485:Allergens; D000941:Antigens; D051197:Toll-Like Receptor 4; D007073:Immunoglobulin E