Yamahana Junya, Wada Takashi, Furuichi Kengo, Sakai Norihiko, Yokoyama Hitoshi, Kaneko Shuichi
Division of Blood Purification, Department of Gastroenterology and Nephrology, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-Machi, Kanazawa 920-8641, Japan.
Nephrol Dial Transplant. 2006 Oct;21(10):2736-44. doi: 10.1093/ndt/gfl431. Epub 2006 Aug 5.
The therapeutic efficacy of the regulation of T helper (Th)-1-predominant immune responses remains to be investigated. Therefore, the effects of the anti-inflammatory compound TAK-603 were investigated in a model of crescentic glomerulonephritis induced by a small dose of nephrotoxic serum in Wistar-Kyoto rats.
TAK-603 (50 mg/kg body weight) was administered orally, starting at the time of induction of glomerulonephritis. In group 1, the drug was administered daily for the initial 6 days. TAK-603 was administered on day 0 only in group 2, and from day 3 to 5 in group 3. In each group, nephritic rats were killed on days 6 and 56.
In group 1 consisting of rats treated with TAK-603 daily from day 0 to 5, glomerular damage, including crescent formation, was improved on day 6, with reductions in the numbers of CD4, CD8 and ED-1 positive cells, as well as in urinary protein excretion. Protein and transcript levels of Th1 cytokines in the diseased kidneys were markedly decreased by TAK-603 treatment. Renal pathology, including glomerulosclerosis and interstitial fibrosis, was ameliorated and proteinuria was markedly decreased. Elevated levels of serum creatinine showed concomitant improvement. In group 3, in which treatment was initiated shortly after the appearance of glomerular abnormalities, glomerular damage was also diminished, resulting in a decrease in urinary protein excretion. Treatment only on the first day in group 2, partially rescued renal dysfunction.
These results suggest the possible therapeutic application of inhibition of Th1-predominant immune responses in progressive crescentic glomerulosclerosis.
调节以辅助性T细胞1（Th1）为主导的免疫反应的治疗效果仍有待研究。因此，在Wistar-Kyoto大鼠小剂量肾毒性血清诱导的新月体性肾小球肾炎模型中，研究了抗炎化合物TAK-603的作用。
从肾小球肾炎诱导时开始口服给予TAK-603（50毫克/千克体重）。在第1组中，药物在最初6天每天给药。在第2组中，TAK-603仅在第0天给药，在第3组中从第3天至第5天给药。每组中，肾炎大鼠在第6天和第56天处死。
在第1组中，从第0天到第5天每天用TAK-603治疗的大鼠，在第6天时肾小球损伤（包括新月体形成）得到改善，CD4、CD8和ED-1阳性细胞数量以及尿蛋白排泄减少。TAK-603治疗使患病肾脏中Th1细胞因子的蛋白质和转录水平显著降低。包括肾小球硬化和间质纤维化在内的肾脏病理得到改善，蛋白尿显著减少。血清肌酐水平升高也随之改善。在第3组中，在肾小球异常出现后不久开始治疗，肾小球损伤也减轻，导致尿蛋白排泄减少。第2组仅在第一天治疗，部分挽救了肾功能障碍。
这些结果表明，在进行性新月体性肾小球硬化中抑制以Th1为主导的免疫反应可能具有治疗应用价值。
