Suppression of experimental crescentic glomerulonephritis by deoxyspergualin.

Abstract

Deoxyspergualin is an immunosuppressive drug which is effective in both preventing allograft rejection and suppressing steroid-resistant acute rejection. This study was designed to determine whether deoxyspergualin could suppress the development of rapidly progressive crescentic glomerulonephritis in antigen-primed animals. Accelerated anti-glomerular basement membrane (GBM) glomerulonephritis was induced by priming rats with rabbit immunoglobulin G (IgG), followed 5 days later by an injection of rabbit anti-rat GBM serum (day 0). Groups of five animals were treated with deoxyspergualin (5 mg/kg.day) or saline by daily ip injection from day 0 until euthanasia on days 1, 7, 14, or 21. Deoxyspergualin treatment resulted in a significant suppression of renal disease. Compared with saline-treated controls, deoxyspergualin treatment reduced proteinuria, resolved hematuria, and completely prevented a fall in creatinine clearance. Deposition of rabbit IgG along the GBM was unaffected by deoxyspergualin treatment, but glomerular deposition of rat IgG and C3 was significantly reduced from day 14 onwards, which was associated with a significant reduction of circulating rat anti-rabbit IgG. Deoxyspergualin treatment also produced a dramatic improvement in renal histology. Glomerular necrosis, fibrosis, and crescent formation were markedly suppressed, whereas tubulointerstitial lesions were completely prevented. This was associated with a marked suppression of mononuclear cell infiltration and activation. In the glomerulus, macrophage infiltration was suppressed by approximately 50%, whereas accumulation of macrophages and immune-activated (interleukin-2 receptor) T cells within the interstitium was almost completely abrogated by deoxyspergualin treatment. In conclusion, deoxyspergualin was found to be effective in suppressing the development of experimental crescentic glomerulonephritis in antigen-primed animals by acting on both the local cell-mediated response within the kidney and the systemic humoral immune response. Further work is warranted to determine whether this could be a useful drug for the treatment of human proliferative glomerulonephritis.