Immunomodulation by thalidomide and thalidomide analogues.

Tumour necrosis factor á (TNFá), a key cytokine involved in the host immune response, also contributes to the pathogenesis of both infectious and autoimmune diseases. To ameliorate the pathology resulting from TNFá in these clinical settings, strategies for the inhibition of this cytokine have been developed. Our previous work has shown that the drug thalidomide is a partial inhibitor of TNFá production in vivo. For example, when leprosy patients suVering from erythema nodosum leprosum (ENL) are treated with thalidomide, the increased serum TNFá concentrations characteristic of this syndrome are reduced, with a concomitant improvement in clinical symptoms. Similarly, we have found that in patients with tuberculosis, with or without HIV infection, short-term thalidomide treatment reduces plasma TNFá levels in association with an accelerated weight gain. In vitro, we have also shown that thalidomide partially inhibits TNFá produced by human peripheral blood mononuclear cells (PBMC) responding to stimulation with lipopolysaccharide (LPS). Recently, we found that thalidomide can also act as a costimulatory signal for T cell activation in vitro resulting in increased production of interleukin 2 (IL2) and interferon ã (IFNã). We also observed a bidirectional eVect on IL12 production: IL12 production is inhibited by thalidomide when PBMC are stimulated with LPS, however, IL12 production is increased in the presence of the drug when cells are stimulated via the T cell receptor. The latter eVect is associated with upregulation of T cell CD40 ligand (CD40L) expression. Thus, in addition to its monocyte inhibitory activity, thalidomide exerts a costimulatory or adjuvant eVect on T cell responses. This combination of eVects may contribute to the immunomodulating properties of the drug. To obtain drugs with increased anti-TNFá activity that have reduced or absent toxicities, novel TNFá inhibitors were designed using thalidomide as template. These thalidomide analogues were found to be up to 50 000 times more active than thalidomide. The compounds comprise two diVerent types of TNFá inhibitors. One class of compounds, shown to be potent phosphodiesterase 4 (PDE4) inhibitors, are selective TNFá inhibitors in LPS stimulated PBMC and have either no eVect or a suppressive eVect on T cell activation. The other class of compounds also inhibit TNFá production, but do not inhibit PDE4 enzyme. These compounds are also potent inhibitors of several LPS induced monocyte inflammatory cytokines. Also, the latter compounds markedly stimulate the anti-inflammatory cytokine IL10. Similarly to thalidomide, these drugs that do not inhibit PDE4 act as costimulators of T cells but are much more potent than the parent drug. The distinct immunomodulatory activity of these new TNFá inhibitors may potentially allow them to be used in the clinic for the treatment of a wide variety of immunopathological disorders of diVerent aetiologies.