IMMUNOMODULATORY ASSAYS TO STUDY STRUCTURE-ACTIVITY-RELATIONSHIPS OF THALIDOMIDE

Thalidomide, which has a long history of tragedy because of its abilit y to cause severe birth defects, is very effective in alleviating eryt hema nodosum leprosum in leprosy patients and aphthous ulcers in AIDS patients. The causes of these inflammatory diseases and the mechanism by which thalidomide diminishes them are unknown. It has been suggeste d that modulation of the immune response plays an important role. We f ound that thalidomide exerts immunomodulatory activity in three bioass ays. It suppresses an IgM plaque forming cell response in mice injecte d with sheep erythrocytes; it inhibits TNF-alpha production by LPS sti mulated human mononuclear cells; and it enhances IL-2 production by Co n-A stimulated human mononuclear cells. We employed these bioassays to compare the activity of 15 analogs of thalidomide with thalidomide it self. Eight of the compounds were derivatives of the glutarimide moiet y of thalidomide and the others were phthalimide or derivatives of the phthalimide moiety of thalidomide. N-hydroxyphthalimide, a simple der ivative of phthalimide, was more effective than thalidomide and was al so the most effective of the compounds assayed in suppressing the IgM plaque and TNF-cr responses, but it did not enhance the IL-2 response, instead, it significantly suppressed it.