A novel antifolate, MX-68, inhibits the development of autoimmune disease in MRL/lpr mice

Abstract

We compared a novel unpolyglutamable antifolate, MX-68, with polyglutamable antifolate, methotrexate (MTX), for treatment of an autoimmune kidney disease which develops spontaneously in MRL/Mp-lpr/lpr (MRL/lpr) mice. Oral administration of either MX-68 or MTX was commenced in 8-week-old female mice and continued 3 times a week until they reached 30 weeks of age. MX-68 delayed the onset of proteinuria and prolonged life span dose-dependently. Furthermore, it suppressed the elevation of serum blood urea nitrogen and cholesterol levels. MX-68 was as effective as MTX at ameliorating events which accompany the development of lupus nephritis, despite that MX-68 did not undergo polyglutamation. These ameliorative effects of MX-68 and MTX did not occur via inhibition of either autoantibody production or cell proliferation. Neither compound suppressed age-dependent elevation of immune complexes or antibodies for single-stranded DNA and TNP in serum nor did they influence the associated enlargement of lymph nodes and spleen. We conclude that MX-68 is beneficial for the treatment of autoimmune kidney disease in mice and may be useful for other related diseases such as systemic lupus erythematosus.