EFFECTS OF A NEW IMMUNOSUPPRESSIVE AGENT, FK506, ON EXPERIMENTAL AUTOIMMUNE UVEORETINITIS IN RATS

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  • 1 August 1988
    • journal article
    • research article
    • Vol. 29  (8) , 1265-1271
Abstract
A comparative study was carried out between cyclosporine and a new immunosuppressive agent, FK506, isolated from the Streptomyces organism. This agent has the capacity to suppress the development of S-antigen-induced experimental autoimmune uveoretinitis (EAU) as well as immune responses to S-antigen in rats immunized with the antigen. When administered daily beginning on the day of immunization and for 14 days thereafter, FK506 at doses between 0.1 and 1 mg/kg suppressed EAU in a dose-dependent manner. Complete inhibition of EAU was achieved at doses of 1, 3 and 10 mg/kg. cyclosporine (1-20 mg/kg) also produced a dose-dependent suppression of EAU and only the highest dose (20 mg/kg) caused complete inhibition of the disease. On the basis of the dose-response study, the capacity of FK506 in preventing EAU induction is 10-30 times more intense than that of cyclosporine. In addition, the FK506 (1 and 3 mg/kg) was found to be effective in preventing EAU even when administered only in the early induction phase (days 0-5) or late effector phase (days 7-12). similar effects were obtained by cyelosporine at a daily dose of 30 mg/kg. Furthermore, none of the rats immunized with S-antigen and treated with FK5-506 (1 mg/kg) on days 0-14 developed EAU when reimmunized with S-antigen on day 30. In contrast, similarly treated rats were fully ssuceptible to the induction of experimental allergic encephalomyelitis, or even to EAU when immunized with another retinal antigen, interphotoreceptor retinoid-binding protein. Therefore, as with cyclosporine, as demonstrated in our previous study, FK506 has the capacity to induce immunological unresponsiveness specific to the S-antigen. Fk506 and cyclosporine markedly suppressed the mitotic response of lymphocytes to S-antigen at immunosuppressive doses that prevented the development of EAU. However, the effects of the two agents on the level of antibody to S-antigen appear to differ from each other: an effective dose of cyclosporine in preventing EAU (10 mg/kg/day) did not affect the antibody titer, while a respective dose of FK506 (0.3 mg/kg/day) or even a lower dose of the agent (0.1 mg/kg/day) exhibited a moderate but significant suppression of the antibody levels to S-antigen.