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

本文观察了他克莫司（FK 506）和环孢菌素A（CyA）对大鼠局灶性肾小球硬化（FGS）的影响。在10 ~ 12周龄的雄性SD大鼠中，通过8次重复注射嘌呤霉素氨基糖苷（PAN）和硫酸鱼精蛋白（PS），形成了半肾切除的FGS。末次注射后10天，肌肉内（i.m.）给予FK 506（1.0 mg/kg/天、0.3 mg/kg/天、0.1 mg/kg/天）、CyA（10 mg/kg/天、3 mg/kg/天）或溶剂。每组56天。每2周检查尿蛋白排泄量和肾功能。在第80天处死大鼠。我们通过免疫过氧化物酶染色评估了白细胞的间质浸润。FK 506和CyA均能减少尿蛋白排泄，且呈剂量依赖性。另一方面，所有给药组的血尿素氮（BUN）水平均升高。FK 506 1.0 mg/kg/d或CyA 10 mg/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。两组均可见明显的肾小管损伤和间质纤维化。CyA 3 mg/kg/d、FK 506 0.3mg/kg/d、0.1mg/kg/d组尿蛋白减少。任何组中常见白细胞抗原阳性细胞的数量均未受到抑制。在FK 506 0.3或0.1 mg/kg/天剂量组中，白细胞介素-2受体（IL-2 r）阳性细胞显著减少。结论：两种药物均为治疗肾脏疾病的最佳剂量，可避免严重的肾毒性。

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.