FK506对阳离子化牛血清白蛋白诱导的大鼠实验性膜性肾小球肾炎的影响。

Effects of FK506 on experimental membranous glomerulonephritis induced by cationized bovine serum albumin in rats.

作者信息

Kobayashi M, Muro K, Yoh K, Kondoh M, Iwabuchi S, Hirayama K, Ishizu T, Kikuchi S, Yamaguchi N, Koyama A

机构信息

Department of Internal Medicine, Institute of Clinical Medicine, University of Tsukuba, Ibaraki, Japan.

出版信息

Nephrol Dial Transplant. 1998 Oct;13(10):2501-8. doi: 10.1093/ndt/13.10.2501.

DOI:10.1093/ndt/13.10.2501

PMID:9794552

Abstract

BACKGROUND

There have been no reports on the effect of FK5 06, a new immunosuppressive agent, on experimental membranous glomerulonephritis (MN) induced by an exogenous antigen. Therefore we investigated the effects of FK506 on MN induced by cationized bovine serum albumin (C-BSA) in rats.

METHODS

Two weeks after the rats were immunized with 1 mg of C-BSA and Freund's complete adjuvant, they received intravenous injections of 3 mg/kg of C-BSA 3 times weekly for 4 weeks. Rats were divided into four groups: group A (n = 5) received intramuscular injections of 3 mg/kg of FK506 daily for 5 days beginning 2 days before the first immunization; group B (n =4) received 1 mg/kg of FK506 daily for 2 weeks beginning 2 weeks after the first immunization; and group C (n =4) received 1 mg/kg of FK506 daily for 2 weeks beginning 4 weeks after the first immunization. Group D (n = 5) received no FK506 and served as the control group. Rats were sacrificed 8 weeks after the first immunization.

RESULTS

Administration of FK506 in the preimmunization stage almost completely suppressed the development of MN in group A. Histological findings in groups B and C were similar to those in group D, the control group. However, urinary protein excretion was significantly lower in group B (24+/-46 mg/day) and C (220+/-44 mg/day) than in group D (330+/-61 mg/day). Expression of intracellular adhesion molecule-1 in glomeruli and the number of leukocyte functioning-associated molecules-1 were significantly decreased in groups A, B, and C compared with the control group. Administration of FK506 was not associated with any significant side-effects or histological abnormalities. The whole-blood trough levels of FK506 in groups B and C were 9.1 ng/ml and 9.2 ng/ml respectively.

CONCLUSIONS

The efficacy of FK506 was significantly increased when the drug was administered in the early phase of immunization in this model. The present study suggests that FK506 may be useful in patients with intractable nephrotic syndrome such as MN.

摘要

背景

新型免疫抑制剂FK506对外源性抗原诱导的实验性膜性肾小球肾炎（MN）的影响尚无相关报道。因此，我们研究了FK506对大鼠阳离子化牛血清白蛋白（C-BSA）诱导的MN的影响。

方法

用1mg C-BSA和弗氏完全佐剂免疫大鼠两周后，每周静脉注射3mg/kg C-BSA 3次，共4周。大鼠分为四组：A组（n = 5）在首次免疫前两天开始每天肌肉注射3mg/kg FK506，共5天；B组（n = 4）在首次免疫两周后开始每天注射1mg/kg FK506，共2周；C组（n = 4）在首次免疫四周后开始每天注射1mg/kg FK506，共2周。D组（n = 5）不注射FK506，作为对照组。首次免疫8周后处死大鼠。

结果

免疫前阶段给予FK506几乎完全抑制了A组MN的发展。B组和C组的组织学结果与对照组D组相似。然而，B组（24±46mg/天）和C组（220±44mg/天）的尿蛋白排泄量明显低于D组（330±61mg/天）。与对照组相比，A、B、C组肾小球内细胞间黏附分子-1的表达和白细胞功能相关分子-1的数量均显著降低。给予FK506未出现任何明显的副作用或组织学异常。B组和C组FK506的全血谷浓度分别为9.1ng/ml和9.2ng/ml。