Leflunomide has been shown to be very effective in preventing and curing several autoimmune
animal diseases. Further, this agent is as effective as
cyclosporin A in preventing the rejection of skin and kidney transplants in rats. Preliminary results from patients suffering from severe cases of
rheumatoid arthritis demonstrated that clinical and immunological parameters could be improved with
leflunomide therapy. Mode of action studies revealed that this substance antagonizes the proliferation inducing activity of several
cytokines and is
cytostatic for certain cell types. In this light, we could show that
tyrosine phosphorylation of the
RR-SRC peptide substrate and the autophosphorylation of the
epidermal growth factor (
EGF) receptor were, dose dependently, inhibited by
leflunomide.
EGF activates the intrinsic
tyrosine kinase of its receptor, which stimulates the phosphorylation of a variety of
peptides, the
amino acid residue in all cases is
tyrosine. These results indicate that much of
leflunomide's activity could be due to the inhibition of
tyrosine-kinase(s), which is an important general mechanism for the proliferation of various cell types. Thus,
leflunomide, which is effective against
autoimmune diseases and reactions leading to graft rejection, would seem to have a mode of action separating it from known immunosuppressive drugs.