Background: 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.
Methods: 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.
Results: 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.
Conclusions: These results suggest the possible therapeutic application of inhibition of Th1-predominant immune responses in progressive crescentic glomerulosclerosis.