| Abstrakt: |
LF15-0195c is a novel chemically synthesized immunosuppressive reagent which is about to undergo a phase II trial in vasculitis in Australia. We examined the ability of LF15 to suppress the development of renal injury in rats with anti-GBM glomerulonephritis. Groups of rats (n = 8) were primed with a s.c. injection of 5 mg sheep IgG. Seven days later (day 0), the rats received an i.v. injection of 10ml/kg of sheep anti-rat GBM serum. Beginning 2h prior to administration of anti-GBM serum, the rats received daily s.c. injections of either 4mg/kg LF15 or normal saline until being sacrificed on day 14. Compared to saline treatment, LF15 prevented the development of proteinuria (248 ± 105 vs 21 ± 25 mg/24h, p < 0.0001; normal 12.5 ± 1.7 mg/24h), reduced serum creatinine (76.1 ± 9.6 vs 62.3 ± 2.6 μM, p = 0.002; normal = 49.1 ± 8.4 μM) and markedly inhibited the pathological damage, including segmental glomerular lesions (49.1 ± 12.3 vs 6.6 ± 10.6%, p < 0.0001), tubular/interstitial damage (score: 2.4 ± 0.8 vs 0.2 ± 0.2, p < 0.0001) and renal fibrosis. LF15 significantly suppressed the immune response in anti-GBM disease in terms of: the antibody response to sheep IgG (↓65%, p< 0.0001), glomerular (↓79%, p < 0.0001) and tubular/interstitial (↓85%, p< 0.0001) leukocyte infiltrate and urine excretion of IL-1β (2.0 ± 0.9 vs 0.8 ± 0.7 ng/24h, p = 0.01) and TGF-β1 (3.1 ± 1.5 vs 0.2 ± 0.5 ng/24h, p < 0.0001). In conclusion, LF15 treatment inhibits rat anti-GMB disease through multiple mechanisms of action. Therefore, LF-15 may have significant therapeutic potential in human glomerulonephritis. [ABSTRACT FROM AUTHOR] |
