Effects of pidotimod on macrophage functions in methylprednisolone-treated mice

CD-1 mice were treated with methylprednisolone (mPDN) 2-5 mg/kg s.c. for 11 or 6 days, in order to achieve an immunosuppressed state. For the same length of time a group of mice also received pidotimod ((R)-3-[(S)-(5-oxo-2-pyrrolidinyl)carbonyl]-thiazolidine-4-carboxylic acid, PGT/1A, CAS 121808-62-6) i.p. at 100 or 10 mg/kg. At the end of treatment, peritoneal macrophages (MO) were recovered, purified by adherence to plastic and activated in vitro with different stimuli. After 24 h of incubation, the supernatants were collected and assayed for the presence of tumor necrosis factor-alpha (TNF-α) and nitrite (NO2-), which is the stable derivative of nitric oxide (NO) in acqueous solution. It is well known that TNF-α and NO represent two out of many molecules secreted by activated MO which are essential for killing microorganisms and for natural response to infections. It was observed that MO from mPDN-treated mice were unable to produce sufficient levels of both TNF-α and NO when stimulated in vitro with lipopolysaccharide, IFN-γ or conidia from an opportunistic fungus, Aspergillus fumigatus, confirming that corticosteroids are able to inhibit the antimicrobial activity of MO. However, MO from mice receiving mPDN plus pidotimod fully recovered the capacity to produce TNF-α and NO in response to the same stimuli. Optimal dose of pidotimod was 100 mg/kg. In addition, pidotimod was also able to reconstitute the cullularity of the peritoneum and of the spleens of mice immunodepressed by mPDN. These results suggest that pidotimod is a very useful drug for improving natural host resistance to infections by modulating the production of cytokines and toxic radicals by activated MO, especially in immunocompromised hosts.