Effects of leflunomide (HWA 486) on expression of lymphocyte activation markers.

Leflunomide (HWA 486), an isoxazol derivative, has been shown to be very effective in combating autoimmune diseases and transplantation rejection in a great number of animal models. The main metabolite of leflunomide, A77 1726, is a potent antiproliferative compound. To further elucidate this effect, lymphocytes of healthy human donors were cultured for 24, 48 or 72 h in the presence of PHA or immobilized anti-CD3 antibody. A77 1726 was added at concentrations between 10 and 100 microM. Flow cytometric evaluation of early activation or proliferation markers (IL-2 and transferrin receptors, respectively) showed that their expression was inhibited in a dose-dependent manner by A77 1726. Together with previous data, these experiments indicate that leflunomide not only inhibits the expansion of already proliferating lymphocytes, but also impairs PHA and anti-CD3 antibody triggered activation of quiescent cells. Thus, this compound may exert its effects through influencing two important aspects of an immune response, that is, activation and proliferation of lymphocytes.