Differential effects of leflunomide on leukocytes: Inhibition of ratin vivo adhesion and humanin vitro oxidative burst without affecting surface marker modulation

Abstract

Leflunomide has been shown to combat effectively autoimmune diseases in a number of animal models, as well as chronic polyarthritis of humans. Here we report on the effects of this novel drug on the adherence of leukocytes to endothelium, an essential event in establishment and maintenance of inflammation. The entry of cells into tissues is dependent on interactions of adhesion molecules. The process of diapedesis, which these molecules control, involves three phases: tethering, triggering of receptors on endothelial cells and firm attachment of leukocytes to these cells. The interaction of LECAM-1 (constitutively expressed on circulating leukocytes) and P- and E-selectins on the vessel wll leads to rolling of leukocytes along the endothelium. Using anin vivo system (rat peritoneum) we found that leflunomide effectively inhibits the rolling of leukocytes along the vessel wall after formyl-methionyl peptide (FMLP) induction. Leflunomide's inhibition of FMLP-induced rolling does not appear to be due to its effects on either LECAM-1 or CD11b, because their modulation was unaltered by this drug. We did, though, find that leflunomide strongly inhibited the FMLP-induced induction of the oxidative burst in these cells. Although we have not yet obtained data on leflunomide's effects on the other phases of diapedesis, our results indicate that this drug has effects on leukocyte activation and adhesion, key events in the initiation and maintenance of chronic inflammation and pathological tissue damage.