The effect of thalidomide on BCG-induced granulomas in mice.

Granuloma proliferation is the result of a series of complex biological events in which a variety of cell types and cytokines are involved. Tumor necrosis factor alpha (TNF-alpha) plays a central role. In the present study, we investigated the effect of thalidomide (alpha-N-pthalimidoglutarimide), a selective inhibitor of TNF-alpha synthesis, on granuloma 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 size 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 levels of thalidomide-treated mice were significantly lower (85%) than control mice on day 14 and remained lower (55%) on days 21 and 28. Positive immunohistochemical staining specific for TNF-alpha were demonstrable only in well-developed granulomas in which central mononuclear cells presented extensive differentiation into epithelioid cells. Daily administration of thalidomide for 21 to 28 days to the BCG-infected mice inhibited local TNF-alpha expression in well-developed granulomas. The mechanisms by which thalidomide modulates the granuloma proliferation are discussed.