LEFLUNOMIDE, A NOVEL IMMUNOSUPPRESSIVE AGENT - THE MECHANISM OF INHIBITION OF T-CELL PROLIFERATION

Leflunomide is a novel immunomodulating drug tha has recently been dem onstrated to prevent acute rejection and reverse ongoing rejection of kidney and cardia allografts in rats. In vitro studies here demonstrat e that leflunomide suppresses proliferation of human PBL stimulated wi th (1) allogeneic PBL in a one-way MLR (50% inhibition with 50-25 muM) ; (2) anti-CD3 mABs plus PMA (50% inhibition with 70 muM leflunomide); and (3) anti-CD28 mABs plus PMA (50% inhibition with 65 muM leflunomi de). In contrast, CsA only inhibited T cell proliferation stimulated b y anti-CD3 plus PMA. Leflunomide partially inhibited IL-2 production o f T cells stimulated with anti-CD3 plus PMA or anti-CD28 plus PMA, whe reas CsA completely inhibited IL-2 production by T cells stimulated by the CD3 pathway and only partially inhibited IL-2 production by T cel ls stimulated by the CD28 pathway. Because comparable levels of IL-2 w ere produced by CD28-stimulated T cells treated with either CsA or lef lunomide, but no inhibition of proliferation was observed in the CsA-t reated cultures, we hypothesized that the lowering of IL-2 levels was not the mechanism by which leflunomide inhibited T cell proliferation. This hypothesis was supported by the observations that exogenous IL-2 failed to restore the T cell proliferation in the presence of lefluno mide. Loss of T cell responsiveness to IL-2 in the presence of lefluno mide was not due loss of expression of IL-2 receptors. Collectively, o ur data suggest that inhibition of T cell proliferation by leflunomide occurs via inhibition of responsiveness to IL-2.