Intranasal Exposure of Mice to House Dust Mite Elicits Allergic Airway Inflammation via a GM-CSF-Mediated Mechanism

Abstract

It is now well established that passive exposure to inhaled OVA leads to a state of immunological tolerance. Therefore, to elicit allergic sensitization, researchers have been compelled to devise alternative strategies, such as the systemic delivery of OVA in the context of powerful adjuvants, which are alien to the way humans are exposed and sensitized to allergens. The objectives of these studies were to investigate immune-inflammatory responses to intranasal delivery of a purified house dust mite (HDM) extract and to evaluate the role of GM-CSF in this process. HDM was delivered to BALB/c mice daily for 10 days. After the last exposure, mice were killed, bronchoalveolar lavage was performed, and samples were obtained. Expression/production of Th2-associated molecules in the lymph nodes, lung, and spleen were evaluated by real-time quantitative PCR and ELISA, respectively. Using this exposure protocol, exposure to HDM alone generated Th2 sensitization based on the expression/production of Th2 effector molecules and airway eosinophilic inflammation. Flow cytometric analysis demonstrated expansion and activation of APCs in the lung and an influx of activated Th2 effector cells. Moreover, this inflammation was accompanied by airways hyper-responsiveness and a robust memory-driven immune response. Finally, administration of anti-GM-CSF-neutralizing Abs markedly reduced immune-inflammatory responses in both lung and spleen. Thus, intranasal delivery of HDM results in Th2 sensitization and airway eosinophilic inflammation that appear to be mediated, at least in part, by endogenous GM-CSF production.

Immunomodulatory Effects of CpG Oligodeoxynucleotides on House Dust Mite-Induced Airway Inflammation in Mice

“…Furthermore, airway remodeling, characterized by severe goblet cell hyperplasia/hypertrophy, subepithelial fibrosis and increases in the level of TGF-β 1 in the BALF was also demonstrated. Although it has been reported that the repeated inoculation of HDM into the trachea or the nose in mice induces airway eosinophilia or hyperresponsiveness [24, 25], our model suggests that repeated HDM instillation to the airway directly promotes Th1/Th2 imbalance in the airway where the indoor allergen was invaded. In addition, we also confirmed that repeated instillation of another foreign protein, OVA, could not induce asthmatic responses at all, and that instillation tolerance was not observed in our model until Der f was instilled 24 times (data not shown).…”

“…However, there are few studies demonstrating its pathophysiological effect via allergenicities in vivo by repeated local instillation of HDM without additional adjuvants [24, 25]. Moreover, the immunomodulatory effects of CpG ODNs on the development of HDM-induced airway inflammation and remodeling have not yet been investigated in vivo, except for a mouse model of allergic rhinitis [26].…”

Upregulation of the Release of Granulocyte-Macrophage Colony-Stimulating Factor from Keratinocytes Stimulated with Cysteine Protease Activity of Recombinant Major Mite Allergens, Der f 1 and Der p 1

“…GM-CSF has many actions relevant to allergic inflammation including AD [26, 27]. In this study, we analyzed whether the stimulation of keratinocytes with the proteolytic activity of rDer f 1 and rDer p 1 upregulates the release of GM-CSF, and if so, whether cystatin A can block this process.…”

Prolonged Ovalbumin Exposure Attenuates Airway Hyperresponsiveness and T Cell Function in Mice

“…Abundant experimental evidence demonstrates that exposure to antigen alone (OVA, DerP1) induces inhalation tolerance, while co-administration of the same antigen with an adjuvant such as aluminum hydroxide, GM-CSF or LPS leads to antigen-specific allergic sensitization [6]. On the other hand, exposure of mice to HDM extract is sufficient for allergic sensitization [32, 33]. This is likely due to the protease activity associated with major allergens [34,35,36,37,38,39].…”