CONTINUOUS ADMINISTRATION OF ANTI-INTERLEUKIN-10 ANTIBODIES DELAYS ONSET OF AUTOIMMUNITY IN NZB W F1-MICE/

We have previously shown that continuous administration of anti-interl eukin 10 (anti-IL-10) antibodies (Abs) to BALB/c mice modifies endogen ous levels of autoantibodies, tumor necrosis factor alpha (TNF-alpha), and interferon gamma, three immune mediators known to affect the deve lopment of autoimmunity in ''lupus-prone'' New Zealand black/white (NZ B/W)F-1 mice. To explore the consequences of IL-10 neutralization in N ZB/W F-1 mice, animals were injected two to three times per week from birth until 8-10 mo of age with anti-IL-10 Abs or with isotype control Abs. Anti-IL-10 treatment substantially delayed onset of autoimmunity in NZB/W Pr mice as monitored either by overall survival, or by devel opment of proteinuria, glomerulonephritis, or autoantibodies. Survival at 9 mo was increased from 10 to 80% in anti-IL-10-treated mice relat ive to Ig isotype-treated controls. This protection against autoimmuni ty appeared to be due to an anti-IL-10-induced upregulation of endogen ous TNF-alpha, since anti-IL-10-protected NZB/W F-1 mice rapidly devel oped autoimmunity when neutralizing anti-TNF-alpha Abs were introduced at 30 wk along with the anti-IL-10 treatment. Consistent with the pro tective role of anti-IL-10 treatment in these experiments, continuous administration of IL-10 from 4 until 38 wk of age accelerated the onse t of autoimmunity in NZB/W F-1 mice. The same period of continuous IL- 10 administration did not appear to be toxic to, or cause development of lupus-like autoimmunity in normal BALB/c mice. These data suggest t hat IL-10 antagonists may be beneficial in the treatment of human syst emic lupus erythematosus.