Lupus nephropathy in New Zealand F1 hybrid mice treated by (-)15-deoxyspergualin

Lupus nephropathy in New Zealand F1 hybrid mice treated by (-)15-deoxyspergualin. The effect of (-)15-deoxyspergualin (15-dsp), a new immunosuppressant which was originally separated from the culture filtrate of a strain of Bacillus laterosporus, was evaluated in this study. Various doses of 15-dsp were subcutaneously administered to New Zealand black/white F1 hybrid mice (B/WF1) four times a week starting at 14 weeks of age, just prior to the onset of nephropathy. The life span of the treated animals, studied at 0.6 to 6.0mg/kg body weights, compared with the control mice was significantly prolonged by 15-dsp treatment (percent survival of the treated mice at 50 to 70 weeks of age was significantly higher than that of the control mice, except that of the 0.6mg group at 60 wks of age, P < 0.05 by Fisher's exact test). In the 6.0mg group of mice, complete suppression of spontaneously progressive splenomegaly with decreased total spleen cells was observed at 24 through 36 weeks of age compared with the same-aged control group of mice (P < 0.01). Absolute numbers of L3T4+ splenocytes determined by flow cytometry, as well as L3T4+/Lyt2+ ratio, were decreased, while in vitro interleukin 2 production by splenocytes induced with staphylococcal enterotoxin A was significantly enhanced. Serum IgG anti-ds DNA antibody levels, measured by radioimmunoassay in the treated mice, were significantly lower at 24 through 36 weeks of age than those in the control mice (P < 0.01), and the incidence of significant proteinuria (≥100 mg/dl) in the 15-dsp group was lower at both 32 and 36 weeks of age (P < 0.001). Glomerular histological score by light microscopy and IgG and C3 deposition determined by immunofluorescence were clearly improved by the 15-dsp treatment at 24 to 36 weeks of age. From these data we may conclude that 15-dsp effectively suppressed the spontaneous polyclonal B cell activation inherent to these lupus prone mice, leading to decreased anti-DNA production and inhibition of subsequent development of nephropathy. Although administration of its high dose causes bone marrow suppression, 15-dsp, which is devoid of known nephrotoxicity, may deserve further evaluation as one of the promising therapeutic agents for glomerulonephritis.