SUPPRESSION OF EXPERIMENTAL CRESCENTIC-TYPE ANTIGLOMERULAR BASEMENT-MEMBRANE (GBM) NEPHRITIS BY FK506 (TACROLIMUS HYDRATE) IN RATS

The effect of FK506 (tacrolims hydrate), an immunosuppressive agent pr oduced by Streptomyces tsukubaensis, on crescentic-type anti-glomerula r basement membrane (GBM) nephritis in rats was investigated. When rat s were treated with FK506 from 1 or 20 days after the anti-GBM serum i njection, FK506 inhibited the increase in urinary protein excretion. H istological observation demonstrated that FK506 suppressed glomerular alterations. In the FK506-treated rats, antibody production and rat-Ig G and C-3 deposits on the GBM were significantly less than those in th e nephritic control group. FK506 treatment suppressed the accumulation of ED-1-positive cells, CD4-positive cells, CD8-positive cells, inter leukin-2 (IL-2)-receptor-positive cells, leukocyte-function-associated antigen-1 (LFA-l)-positive cells and intercellular adhesion molecule- 1 (ICAM-1)-expression in nephritic glomeruli. However, in the in vitro study, FK506 failed to inhibit the up-regulated ICAM-1 expression on endothelial cells in response to tumor necrosis factor (TNF)-alpha. On the other hand, IL-2 production from the spleen cells isolated from n ephritic rats treated with FK506 was lower than that in the nephritic control rats. These results suggest that FK506 is effective against cr escentic-type anti-GBM nephritis and that the antinephritic mechanisms of FK506 is due to the inhibition of intraglomerular accumulation and activation of leukocytes through the suppression of ICAM-1 expression and IL-2 production.