Effects of immunosuppresants on the activated-T cell infiltration mediating progression of glomerular lesions

研究了他克莫司（FK506）和环孢素A （CyA）对大鼠实验性局灶性肾小球硬化（FGS）的影响。10 ~ 12周龄半肾切除的雄性sd大鼠经8次反复注射嘌呤霉素氨基核苷（PAN）和硫酸鱼精蛋白（PS）后发生FGS。末次给药后10 d，各组分别肌注FK506 （1.0mg/kg/day、0.3mg/kg/day、0.1mg/kg/day）、CyA （10mg/kg/day、3mg/kg/day）或载药（ig），连续56 d。每两周检查尿蛋白排泄和肾功能。第80天处死大鼠。我们通过免疫过氧化物酶染色评估白细胞间质浸润情况。FK506和CyA均能减少尿蛋白的排泄。另一方面，所有给药组的血尿素氮（BUN）水平均升高。FK506 1.0mg/kg/d或CyA 10mg/kg/d剂量组血清肌酐（sCr）水平显著升高，肌酐清除率（CCr）显著降低。两组均有明显的小管损伤和间质纤维化。同时，CyA 3mg/kg/d、FK506 0.3mg/kg/d和0.1mg/kg/d给药组尿蛋白降低。各组白细胞抗原阳性细胞数均未受抑制。FK506 0.3、0.1 mg/kg/d组白细胞介素-2受体（IL-2r）阳性细胞显著减少。我们的结论是，两种药物的最佳剂量可用于肾脏疾病，并避免严重的肾毒性。

We investigated the effect of Tacrolimus (FK506) and Cyclosporin A (CyA) on experimental focal glomerulosclerosis (FGS) in rats. FGS developed in heminephrectomized 10 to 12 week-old male Sprague-Dawley rats by eight repeated injection of puromycin aminonucleosid (PAN) and protamine sulfate (PS). Ten days after the last injection, FK506 (1.0mg/kg/day, 0.3mg/kg/day, 0.1mg/kg/day), CyA (10mg/kg/day, 3mg/kg/day) or vehicle was administered intramuscularly (i.m.) in each group for 56 days. Urinary protein excretion and renal function were examined every two weeks. Rats were sacrificed at day 80. We evaluated interstitial infiltration of leucocytes by an immunoperoxidase staining. Both FK506 and CyA reduced urinary protein excretion dependent to their doses. On the other hand, blood urea nitrogen (BUN) level elevated in all administered groups. At a dose of FK506 1.0mg/kg/day or CyA 10mg/kg/day, serum creatinine (sCr) levels elevated and creatinine clearance (CCr) decreased significantly. In these two groups, tubular injuries and interstitial fibrosis were obviously founded. Meanwhile CyA 3mg/kg/day, FK506 0.3mg/kg/day or 0.1mg/kg/day administered groups showed the decrease of urinary protein. Number of common leucocyte antigen positive cells were not inhibited in any groups. Interleukin-2 receptor (IL-2r) positive cells were decreased significantly in FK506 0.3 or 0.1 mg/kg/day groups. We conclud that optimal dose of both drugs are available for renal disease and avoid serious nephrotoxicity.