THE EFFECT OF THALIDOMIDE ON BCG-INDUCED GRANULOMAS IN MICE

Granuloma proliferation is the result of a series of complex biologica l events in which a variety of cell types and cytokines are involved. Tumor necrosis factor alpha (TNF-alpha) plays a central role. In the p resent study, we investigated the effect of thalidomide (alpha-N-pthal imidoglutarimide), a selective inhibitor of TNF-alpha synthesis, on gr anuloma formation during BCG infection in Oncins France 1 (OF-1) mice. Subcutaneous injections of 30 mg/kg body weight of thalidomide daily for 14, 21 or 28 days into the mice resulted in the reduction of the s ize and total number of liver granulomas. The most striking effect of thalidomide was observed after 28 days, when the total number of liver granulomas was reduced by as much as 40% (P<0.05). Serum TNF-alpha le vels of thalidomide-treated mice were significantly lower (85%) than c ontrol mice on day 14 and remained lower (55%) on days 21 and 28. Posi tive immunohistochemical staining specific for TNF-alpha was demonstra ble only in well-developed granulomas in which central mononuclear cel ls presented extensive differentiation into epithelioid cells. Daily a dministration of thalidomide for 21 to 28 days to the BCG-infected mic e inhibited local TNF-alpha expression in well-developed granulomas. T he mechanisms by which thalidomide modulates the granuloma proliferati on are discussed.