Effects of cyclosporin A and a rapamycin derivative (SAR943) on chronic allergic inflammation in sensitized rats

Abstract

SUMMARYImmunomodulators such as cyclosporin A (CsA) and SAR943 (32-deoxorapamycin) inhibit single allergen-induced allergic in¯ammation such as eosinophilic and lymphocytic in®ltration and mRNA expression for interleukin (IL)-4 and IL-5. We examined the effects of CsA and SAR943, administered orally, on asthmatic responses in a rat model of chronic allergic in¯amma-tion. Sensitized Brown-Norway (BN) rats were exposed to ovalbumin (OVA) aerosol every third day on six occasions. CsA (5 mg/kg/day), SAR943 (2Á5 mg/kg/day) or vehicle (Neoral TM ) was administered orally, once a day, from days 10 to 21 (a total of 12 doses). We measured eosinophilic and T-cell in¯ammation in the airways, proliferation of airway cells by incorporation of bromodeoxyuridine (BrdU) and bronchial responsiveness to acetylcholine. CsA had no effects, while SAR943 inhibited airway smooth muscle (ASM, P < 0Á05) and epithelial cell (P < 0Á01) BrdU incorporation, and the number of CD4T cells (P < 0Á05), without effects on BHR. ASM thickness was not signi®cantly increased following chronic allergen exposure. Therefore, CsA and SAR943 have no effect on chronic eosinophilic in¯ammation, while SAR943, but not CsA, had a small effect on the proliferation of ASM and epithelium.

The Efficacy and Safety of Long-term Oral Cyclosporine Treatment for Patients with Atopic Dermatitis

“…However, another report showed that CsA treatment was associated with down-regulation of IgE production via suppressing the secretion of such Th2 cytokines as IL-4 and IL-5 25 . In our study, the serum level of total IgE was significantly decreased after the CsA treatment.…”

Targeting of protein translation as a new treatment paradigm for prostate cancer

“…Although rapamycin exhibited potent antitumor effects in experimental tumor models, it failed to demonstrate promise as an anticancer drug in clinical trials [85–87]. Hence, rapamycin analogues (rapalogues) with more favorable pharmaceutical characteristics such as RAD001 (Everolimus), CCI-779 (Temsirolimus), AP23573 (Deforolimus), SAR943 (32-deoxorapamycin) and ABT-578 (Zotarolimus) have been developed [51, 52, 88, 89]. RAD001 and CCI-779 have been approved by the FDA for the treatment of advanced renal cell carcinoma [53,90].…”

“…These second generation (catalytic) mTOR inhibitors can effectively minimize the feedback activation of Akt by mTORC2 to avoid offsetting their effects of sequestering eIF4E. Importantly, they inhibit 4E-BP phosphorylation more strongly than rapamycin and rapalogues [88]. Another potential class of mTOR kinase inhibitors is the dual PI3K/mTOR inhibitors.…”

Rapamycin inhibition of eosinophil differentiation attenuates allergic airway inflammation in mice

“…In some studies, rapamycin has been suggested to inhibit pathological changes of allergic asthma, including airway hyperresponsiveness (AHR), eosinophilic airway inflammation, goblet cell hyperplasia and IgE production; [7][8][9][10] however, other works have also shown that it has little effects on the allergic airway inflammation and AHR. [11][12][13] Most importantly, the underlying mechanisms that mediated the effects of rapamycin in the process of allergic asthma remain largely unknown.…”