PREVENTIVE EFFECT OF A NOVEL ANTIFOLATE, MX-68, IN MURINE SYSTEMIC LUPUS-ERYTHEMATOSUS (SLE)

We evaluated the preventive effects of a novel nonpolyglutamatable ant ifolate, MX-68, on two experimental murine models of systemic lupus er ythematosus (SLE); NZBxNZW F1 (BWF1) mice and chronic graft-versus-hos t disease (GVHD) mice, in comparison with classical antifolate methotr exate (MTX). The oral administration of 2 mg/kg MX-68, three times a w eek from 12 to 40 or 60 weeks of age, significantly delayed the onset of proteinuria and prolonged the life-span of BWF1 mice. The elevation of serum blood urea nitrogen (BUN) and cholesterol levels resulting f rom the development of lupus nephritis was also inhibited. However, MX -68 did not suppress the increase of serum anti-DNA or anti-TNP antibo dies or total IgG isotype (IgG1, IgG2 and IgG3) levels. In chronic GVH D mice, MX-68 given three times a week from the day of first cell inje ction, for 9 weeks, dose-dependently delayed the appearance of protein uria. The elevation of BUN and cholesterol levels was also inhibited. Furthermore, in the 4 mg/kg MX-68 group, the production of IgG anti-DN A and anti-TNP antibodies was significantly inhibited, but this was no t observed in the 2 mg/kg MX-68 and the 4 mg/kg MTX groups. These bene ficial effects of MX-68 were much greater than those of MTX in both mo dels. These results suggest that MX-68 might be a more useful drug for the treatment of SLE. (C) 1997 International Society for Immunopharma cology.