Differential Effects of Rapamycin and Dexamethasone in Mouse Models of Established Allergic Asthma

Abstract

The mammalian target of rapamycin (mTOR) plays an important role in cell growth/differentiation, integrating environmental cues, and regulating immune responses. Our lab previously demonstrated that inhibition of mTOR with rapamycin prevented house dust mite (HDM)-induced allergic asthma in mice. Here, we utilized two treatment protocols to investigate whether rapamycin, compared to the steroid, dexamethasone, could inhibit allergic responses during the later stages of the disease process, namely allergen re-exposure and/or during progression of chronic allergic disease. In protocol 1, BALB/c mice were sensitized to HDM (three i.p. injections) and administered two intranasal HDM exposures. After 6 weeks of rest/recovery, mice were re-exposed to HDM while being treated with rapamycin or dexamethasone. In protocol 2, mice were exposed to HDM for 3 or 6 weeks and treated with rapamycin or dexamethasone during weeks 4–6. Characteristic features of allergic asthma, including IgE, goblet cells, airway hyperreactivity (AHR), inflammatory cells, cytokines/chemokines, and T cell responses were assessed. In protocol 1, both rapamycin and dexamethasone suppressed goblet cells and total CD4+ T cells including activated, effector, and regulatory T cells in the lung tissue, with no effect on AHR or total inflammatory cell numbers in the bronchoalveolar lavage fluid. Rapamycin also suppressed IgE, although IL-4 and eotaxin 1 levels were augmented. In protocol 2, both drugs suppressed total CD4+ T cells, including activated, effector, and regulatory T cells and IgE levels. IL-4, eotaxin, and inflammatory cell numbers were increased after rapamycin and no effect on AHR was observed. Dexamethasone suppressed inflammatory cell numbers, especially eosinophils, but had limited effects on AHR. We conclude that while mTOR signaling is critical during the early phases of allergic asthma, its role is much more limited once disease is established.

Kinases as Novel Therapeutic Targets in Asthma and Chronic Obstructive Pulmonary Disease

“…However, rapamycin is very effective in inhibiting mTOR activation in COPD lung and PBMC, which results in reduced corticosteroids resistance (Mitani et al, 2015). In addition, rapamycin is effective in suppressing allergic inflammation in sensitized mice and inhibits eosinophil differentiation (Mushaben et al, 2013;Hua et al, 2015). Interestingly, rapamycin switches the phenotype of lymphocytes from Th2 to regulatory T cells (Foxp3 + ) .…”

Aligning mouse models of asthma to human endotypes of disease

“…Often, but not always, the IL‐17A/Th17 response is involved in promoting neutrophil recruitment, yet its role in promoting AHR varies depending on the model, ranging from pathogenic to protective . In general, exogenously derived Th17 cells promote AHR and the development of GC‐resistant disease, whereas in more Th2‐driven models, the Th17 response contributes less to disease pathology and AHR development . In some models, the endogenously generated Th17 response negatively regulates the Th2 response and is protective against AHR development, whereas in a model of epicutaneous sensitization to OVA antigen, the Th17 response is pathogenic, recruiting neutrophils to the airway and promoting AHR development …”

A New Era of Targeting the Ancient Gatekeepers of the Immune System: Toll-Like Agonists in the Treatment of Allergic Rhinitis and Asthma

“…Interestingly, transcriptional factors activated through TLR signaling (e.g. NF-κB) are redox sensitive and several anti-oxidant agents have been demonstrated to inhibit asthma symptoms by reduction of reactive oxygen species generation [21,22,23,24]. In addition, the consumption of probiotics, which has been proposed to prevent allergic diseases, might work via modulation of TLRs [25,26,27].…”