Suppression of experimental crescentic-type anti-glomerular basement membrane (GBM) nephritis by FK506 (tacrolimus hydrate) in rats.
The effect of FK506 (tacrolims hydrate), an immunosuppressive agent produced by Streptomyces tsukubaensis, on crescentic-type anti-glomerular basement membrane (GBM) nephritis in rats was investigated. When rats were treated with FK506 from 1 or 20 days after the anti-GBM serum injection, FK506 inhibited the increase in urinary protein excretion. Histological observation demonstrated that FK506 suppressed glomerular alterations. In the FK506-treated rats, antibody production and rat-IgG and C3 deposits on the GBM were significantly less than those in the nephritic control group. FK506 treatment suppressed the accumulation of ED-1-positive cells, CD4-positive cells, CD8-positive cells, interleukin-2 (IL-2)-receptor-positive cells, leukocyte-function-associated antigen-1 (LFA-1)-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 nephritic rats treated with FK506 was lower than that in the nephritic control rats. These results suggest that FK506 is effective against crescentic-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.
Hayashi
K
K
Department of Pharmacology, Meijo University, Nagoya, Japan.
Nagamatsu
T
T
Ito
M
M
Suzuki
Y
Y
D000818:Animals; D000910:Antibodies, Heterophile / Q000378:metabolism; D001485:Basement Membrane / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D003176:Complement C3 / Q000378:metabolism; D007074:Immunoglobulin G / Q000378:metabolism; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D007678:Kidney Glomerulus / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D007962:Leukocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008297:Male; D009393:Nephritis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D011507:Proteinuria / Q000652:urine; D051381:Rats; D017207:Rats, Sprague-Dawley; D015375:Receptors, Interleukin-2 / Q000378:metabolism; D016559:Tacrolimus / Q000494:pharmacology*
D000910:Antibodies, Heterophile; D003176:Complement C3; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D015375:Receptors, Interleukin-2; D018799:Intercellular Adhesion Molecule-1; D016559:Tacrolimus