A novel non-polyglutamable anti-folate, MX-68, inhibits the induction of experimental autoimmune uveitis in rats.
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.
Hiraoka
M
M
First Department of Internal Medicine, School of Medicine, Tokyo Medical & Dental University, Japan.
Mihara
M
M
Takeda
Y
Y
Miyasaka
N
N
D015074:2-Aminoadipic Acid / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000818:Animals; D019393:Arrestin / Q000494:pharmacology; D001169:Arthritis, Experimental / Q000188:drug therapy; D001327:Autoimmune Diseases / Q000517:prevention & control*; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D003094:Collagen; D003208:Concanavalin A / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005493:Folic Acid Antagonists / Q000627:therapeutic use*; D007114:Immunization; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008214:Lymphocytes / Q000187:drug effects; D008727:Methotrexate / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051381:Rats; D011919:Rats, Inbred Strains; D014605:Uveitis / Q000517:prevention & control*
D019393:Arrestin; D005493:Folic Acid Antagonists; D007166:Immunosuppressive Agents; C104193:N-(1-((2,4-diamino-6-pteridinyl)methyl)-3,4-dihydro -2H-1,4-benzothiazine-7-carbonyl)-L-2-aminoadipic acid; D003208:Concanavalin A; D015074:2-Aminoadipic Acid; D003094:Collagen; D008727:Methotrexate