Anti-CD69 monoclonal antibody treatment inhibits airway inflammation in a mouse model of asthma

Abstract

Abstract:Objective: Airway inflammation and airway hyper-responsiveness (AHR) are principle pathological manifestations of asthma. Cluster of differentiation 69 (CD69) is a well-known co-stimulatory factor associated with the activation, proliferation as well as apoptosis of immune cells. This study aims to examine the effect of anti-CD69 monoclonal antibody (mAb) on the pathophysiology of a mouse model of asthma. Methods: A murine model of ovalbumin (OVA)-induced allergic airway inflammation was used in this study. Briefly, mice were injected with 20 μg chicken OVA intraperitoneally on Days 0 and 14, followed by aerosol provocation with 1% (0.01 g/ml) OVA on Days 24, 25, and 26. Anti-CD69 mAb or isotype IgG was injected intraperitoneally after OVA challenge; dexamethasone (DXM) was administrated either before or after OVA challenge. AHR, mucus production, and eosinophil infiltration in the peribronchial area were examined. The levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-5 (IL-5) in bronchoalveolar lavage fluid (BALF) were also assayed as indices of airway inflammation on Day 28 following OVA injection. Results: Pretreatment with DXM together with anti-CD69 mAb treatment after OVA provocation completely inhibited AHR, eosinophil infiltration and mucus overproduction, and significantly reduced BALF IL-5. However, treatment with DXM alone after OVA challenge only partially inhibited AHR, eosinophil infiltration and mucus overproduction, and did not diminish BALF IL-5. Treatment with either DXM or anti-CD69 mAb did not alter the concentration of BALF GM-CSF. Conclusions: Anti-CD69 mAb treatment inhibits established airway inflammation as effectively as DXM pretreatment. This study provides a potential alternative therapeutic opportunity for the clinical management of asthma and its exacerbation.

Crucial role for CD69 in allergic inflammatory responses: CD69‐Myl9 system in the pathogenesis of airway inflammation

“…The adoptive transfer of ectopic CD69-expressing Cd69 −/− CD4 T cells into Cd69 −/− host mice developed airway inflammation upon OVA inhalation, indicating that CD69 expression on CD4 T cells is sufficient for the induction of airway inflammation, at least in our model. 42,70 Recently this result was followed and supported by another group, 71 in which the pretreatment with dexamethasone (DXM) together with anti-CD69 Ab treatment after OVA exposure completely inhibited airway inflammation; simple anti-CD69 Ab treatment inhibited established airway inflammation as effectively as DXM pretreatment. 71 It is apparent that CD69 plays crucial roles in the infiltration and/or maintenance of inflammatory cells in inflamed tissues; whereas, there may also be a possibility that CD69 is involved in efficient immune responses, especially during the early priming phase, since CD4 T cells from Cd69 −/− mice showed less ability to differentiate into Th2 cells under in vitro culture conditions using APCs and also under in vivo inflammatory conditions.…”

“…42,70 Recently this result was followed and supported by another group, 71 in which the pretreatment with dexamethasone (DXM) together with anti-CD69 Ab treatment after OVA exposure completely inhibited airway inflammation; simple anti-CD69 Ab treatment inhibited established airway inflammation as effectively as DXM pretreatment. 71 It is apparent that CD69 plays crucial roles in the infiltration and/or maintenance of inflammatory cells in inflamed tissues; whereas, there may also be a possibility that CD69 is involved in efficient immune responses, especially during the early priming phase, since CD4 T cells from Cd69 −/− mice showed less ability to differentiate into Th2 cells under in vitro culture conditions using APCs and also under in vivo inflammatory conditions. 70 Since the CD69 cytosolic tail may have some signaling potential, as we described in the previous section, the CD69 molecule itself may contribute to the activation of T cells and Th2 cell differentiation, which is known to be efficiently induced by strong TCR-mediated signaling.…”

A Potential circRNA-miRNA-mRNA Regulatory Network in Asthmatic Airway Epithelial Cells Identified by Integrated Analysis of Microarray Datasets

“…Cahill et al reported that both airway hyperresponsiveness and mast cell counts were decreased in patients with severe asthma after treated with imatinib, a KIT inhibitor (Cahill et al, 2017). It was also reported that anti-CD96 mAb treatment could inhibit established airway inflammation as effectively as dexamethasone pretreatment in a mouse model of asthma (Wang et al, 2015). Sakai et al found that the antagonist of ADRA2A might participate in the inhibition of the allergen provoked late asthmatic response (Sakai et al, 1995).…”

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“…Airway remodeling, characterized by thickening of the airway wall, can have profound consequences for the mechanics of airway narrowing and can contribute to the chronic progression of the disease. [1][2][3][4][5] Allergic asthma is a clinical syndrome characterized by T helper cell (Th)1/Th2 imbalance. [6] Histamine is stored in granules within mast cells and basophils, where it is closely associated with the anionic proteoglycans heparin (in mast cells) and chondroitin-4-sulfate (in basophils).…”