Mammalian target of rapamycin signaling occurs downstream of the PI3K-signaling cascade and is known to play a major role in growth/differentiation, cell metabolism, and survival in many different cell types. More recent work has demonstrated an important role for mTOR in T cell proliferation and differentiation. An inhibitor of mTOR, rapamycin, is already used clinically as an immunosuppressant to prevent organ Lomitapide Mesylate rejection after transplantation. In addition, the use of rapamycin in patients suffering from the destructive lung disease, lymphangioleiomyomatosis, has demonstrated promise in its ability to reduce disease symptoms and stabilize lung function. Previously, our lab demonstrated that inhibition of mTOR with rapamycin prevented Mepiroxol allergic asthma in a mouse model induced by exposure to the allergen, house dust mite. In these studies, rapamycin prevented the allergic response and still suppressed many key asthma characteristics after allergic sensitization was established. Although this study showed that mTOR inhibition could suppress allergic asthma early in the disease process, the role of mTOR during allergen reexposure and chronic, established allergic disease remained unclear. The goal of this study was to determine whether inhibition of mTOR with rapamycin would attenuate key characteristics of allergic asthma in two models that addressed chronic/established disease, namely allergen re-exposure and disease progression. In addition to rapamycin, mice were also treated with the steroid, dexamethasone, for comparison purposes since steroids are currently a mainstay therapy for chronic asthma. We hypothesized that rapamycin and dexamethasone would suppress asthma exacerbations during allergen re-exposure and suppress progressive/ongoing allergic disease by inhibiting T cells. To test this hypothesis, mice in protocol one, which was designed to mimic the effects of allergen re-exposure in a previously sensitized individual, were sensitized to HDM by i.p. injection and then exposed to intranasal HDM to induce asthma. Then, after a 6 week rest/recovery period, mice were re-exposed to HDM while being treated with rapamycin or dexamethasone. In protocol two, to address the role of mTOR in chronic/established allergic asthma, mice were exposed to HDM for 6 weeks and treated with rapamycin or dexamethasone from weeks 4 to 6 of the exposure period. Endpoints assessed included allergen specific IgE, AHR, inflammatory cells, goblet cell metaplasia, cytokine/chemokine levels, and T cell numbers. The goal of our study was to determine whether mTOR inhibition 
with rapamycin would suppress the key features and mediators of HDM-induced allergic asthma in established asthmatic disease. In addition, we also compared rapamycin to the steroid, dexamethasone, since steroids are currently a mainstay treatment for asthma. In the first protocol, we assessed whether rapamycin or dexamethasone could suppress allergic disease during allergen re-exposure. Although rapamycin suppressed IgE levels, goblet cells, and total lung T cells, it had no effect on AHR or BALF cellularity and IL-4 and eotaxin 1 levels were actually augmented. Dexamethasone suppressed goblet cells and total lung T cells, but had no effect on IgE or AHR and only slightly reduced BALF eosinophilia. Our second protocol assessed whether rapamycin or dexamethasone could reverse or inhibit the progression of asthmatic responses during chronic allergic airway disease. In this model, rapamycin did not suppress AHR or goblet cells and actually augmented inflammatory cell numbers, IL-4 and eotaxin 1 levels in the BALF.