LF15-0195 prevents the induction and inhibits the progression of rat anti-GBM disease

Background. LF15-0195 is a novel immunosuppressant that is currently in pha se II clinical trials for the treatment of vasculitis. This study examined whether LF15-0195 could suppress the induction and progression of rat anti- glomerular basement membrane (anti-GBM) glomerulonephritis. Methods. Rapidly progressive glomerulonephritis was induced in primed rats by the administration of anti-GBM serum. In the first experiment, LF15-0195 was given daily by subcutaneous injection (days 0 to 14) to treat the indu ction of anti-GBM disease analyzed at day 14. In a second experiment, rats received LF15-0195 as an intervention treatment from days 7 to 28 (continuo us therapy) or days 7 to 12 (pulse therapy) to treat the progression of dis ease assessed at day 28. Results. Continuous LF15-0195 treatment during the induction of anti-GBM di sease (experiment 1) prevented proteinuria and loss of renal function. and markedly reduced histological kidney lesions and renal fibrosis. LF15-0195 also reduced kidney leukocyte infiltrate, urine excretion of interleukin-1 beta (IL-1 beta) and transforming growth factur-beta (TGF-beta), and the se rum antibody response, but not kidney deposition of Ig and C3. When LF15-01 95 treatment was initiated at day 7, both continuous and pulse therapy part ially inhibited disease progression by suppressing the loss of renal functi on, interstitial macrophage and T-cell accumulation, tubular cell prolifera tion, and renal fibrosis. Conclusion. LF15-0195 prevents the induction and suppresses the progression of rat anti-GBM disease through multiple mechanisms of action. suggesting that this drug may have significant therapeutic potential in human glomerul onephritis. The similar efficacy of continuous and pulse intervention treat ment in this model indicates that short-term LF15-0195 treatment may achiev e optimal benefit without prolonged bone marrow suppression.