MX-68 is a novel
antifolate which is chemically designed not to undergo intracellular polyglutamation thus preventing the development of adverse effects. The present study was carried out to examine both the in vitro and in vivo effects of
MX-68 on experimental autoimmune
uveitis (EAU) and to compare its effect on
collagen-induced arthritis (CIA) in rats. EAU was induced by injecting Lewis rats with
retinal S-antigen in complete
Freund's adjuvant. Either
MX-68 or
methotrexate (MTX), which forms several polyglutamates intracellularly, was orally administered five days a week for three weeks beginning on the day of immunization. In vivo, both
MX-68 and MTX significantly delayed the onset of EAU and inhibited the antibody response to S-
antigen in a dose-dependent manner. High dose
MX-68 (2.5 mg kg-1 day-1) completely abrogated the induction of EAU. No adverse effects were observed in either MX-68- or MTX-treated rats. However, the cessation of
MX-68 administration after a period of three weeks resulted in the induction of EAU. In contrast, both
MX-68 and MTX suppressed the severity of CIA without affecting the onset of the disease and inhibited anti-
collagen antibody production in a dose-dependent fashion. Discontinuation of the drugs did not result in the recurrence of CIA. In vitro, both
MX-68 and MTX significantly suppressed the proliferation of S-
antigen- and Con A-stimulated lymph node cells obtained from immunized rats in a dose-dependent fashion. These data suggest that
MX-68 may be useful for the treatment of
autoimmune diseases including EAU and that the pathophysiology of EAU could be different from that of CIA.