Kivonat:
BACKGROUND: 4SC-101 is a novel dihydroorotate dehydrogenase
inhibitor and a blocker of interleukin (IL)-17 secretion with
beneficial effects in experimental lupus and inflammatory bowel
disease. Its immunomodulatory effect on acute kidney rejection
is not known; therefore, in this study, the impact of 4SC-101
was examined in a rat model of acute kidney rejection. METHODS:
The kidneys of Brown-Norway rats were orthotopically
transplanted into bilaterally nephrectomized Lewis recipients.
Allograft recipients were administered with 4SC-101 at dosages
of 4, 20, or 60 mg/kg per day, and survival was assessed. In the
second setting, the animals were harvested 3 or 5 days after
transplantation (Tx), and graft histologic diagnosis was
determined. The effects of 4SC-101 on impaired renal function
were examined in a model of 5/6 nephrectomy in Lewis rats.
RESULTS: The recipients treated with 20-mg/kg 4SC-101 showed
prolonged survival compared with placebo-treated animals
(mean+/-SEM, 24+/-9.3 vs. 5.4+/-3 days), paralleled by less
severe histologic features of acute kidney rejection such as
interstitial/perivascular infiltration and tubulitis 3 and 5
days after Tx, and a lower level of IL-17 messenger RNA 5 days
after Tx compared with the placebo-treated animals. In the 5/6
nephrectomy model, 20-mg/kg 4SC-101 reduced proteinuria,
glomerulosclerosis, and fibrosis with decreased IL-17 messenger
RNA expression. CONCLUSIONS: 4SC-101 prolongs survival after
Tx, paralleled by amelioration of histologic signs of acute
rejection. Furthermore, it showed no worsening effects on kidney
function in a remnant kidney model and even slowed the
progression of proteinuria and kidney fibrosis. Therefore, 4SC-
101 might be a promising pharmaceutical agent in Tx medicine for
further investigations.