New treatments are needed for the 5 to 10 % of severe asthmatics who are not well controlled despite treatment with standard therapy. These severe asthmatics have persistent asthma symptoms and recurrent disease exacerbations despite treatment with high-doses of inhaled corticosteroids plus long-acting β2-agonists or oral corticosteroids. In addition, the utilization of oral corticosteroids are associated with serious and potentially debilitating side effects, such as diabetes, hypertension, weight gain, impaired host defense, reduced bone density, cataracts, skin atrophy, and myopathy. Limited alternative treatment options exist for these severe, refractory asthmatics. This project is investigating whether pharmacological agents that are in use for other disorders can be utilized for the treatment of asthma. In addition, new therapeutic approaches that are in pre-clinical development may be assessed. This project has shown that rapamycin has paradoxical effects on experimental house dust mite-induced asthma and treatment of established asthma exarcerbated airway hyper reactivity and airway inflammation. This suggests that use of rapamycin to inhibit mTORC1 may not be efficacious for the treatment of established house dust mite-induced asthma (PLoS ONE 2012; 7, e33984). We have also shown that pharmacological inhibition of DNA-dependent protein kinase attenuates experimental house dust mite-induced asthma. DNA-dependent protein kinase (DNA-PK) mediates double stranded DNA break repair, V(D)J recombination, and immunoglobulin class switch recombination, as well as innate immune and pro-inflammatory responses. However, there is limited information regarding the role of DNA-PK in adaptive immunity mediated by dendritic cells (DCs), which are the primary antigen-presenting cell in allergic asthma. We have shown that house dust mite (HDM) induces DNA-PK phosphorylation, which is a marker of DNA-PK activation, in DCs via the generation of intracellular reactive oxygen species. We also demonstratde that pharmacological inhibition of DNA-PK, as well as the specific deletion of DNA-PK in DCs, attenuated the induction of allergic sensitization and Th2 immunity via a mechanism that involved the impaired presentation of HDM antigens. Furthermore, pharmacological inhibition of DNA-PK following antigen priming similarly reduced the manifestations of HDM-induced airway disease. Collectively, these findings suggest that DNA-PK might be targeted as a new treatment for allergic asthma. This project was a collaborative project with Dr. Jay Chung and was published in Nature Communications (2015. 6:6224 doi: 10.1038/ncomms7224.)
