Leflunomide (HWA 486) inhibits experimental autoimmune tubulointerstitial nephritis in rats

Experimental tubulointerstitial nephritis (TIN), induced in Brown Norway rats, is an autoimmune disorder in which afflicted animals display high levels of serum autoantibodies directed against antigens present on the tubular basement membrane (TBM). Serious functional damage, due to lesions of the kidney cortex, is evident 10 days after disease initiation. In an earlier study, we could show that cyclosporin A (CsA), an immunosuppressive drug, effectively prevented the onset of this illness, although it did not inhibit the formation of TBM autoantibodies. In the present study, the protective effects of CsA in autoimmune TIN was compared to those of drugs currently used to combat inflammatory ailments (i.e. prednisolone, indomethacin, naproxen, azathioprine) and a novel immunomodulating agent, leflunomide (HWA 486). Leflunomide is known to specifically inhibit the formation of T-dependent antibodies and is effective in preventing and curing animal autoimmune diseases, i.e. adjuvant arthritis disease of rats and murine lupus-like disorders. We found that not only could leflunomide inhibit TIN, but the drug-effects seemed to be more effective than those of CsA. Further, leflunomide was extremely effective in inhibiting the formation of autoantibodies to TBM, whereas CsA displayed only partial suppression. Neither prednisolone, indomethacin nor naproxen were effective in reducing the autoantibody titer, and did not offer any protection to the development of this disease. Together with the known effects on other autoimmune diseases we conclude that leflunomide is a novel immunointerventive drug protecting against several types of autoimmunity.