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SummaryInterleukin 10 (I1:10) decreases production of 11:1, II:6, and tumor necrosis factor c~ (TNF-ot) in vitro, and neutralization of II:10 in mice leads to elevation of the same monokines. We test here whether this monokine-suppressing property of I1:10 confers on it the capacity to protect mice from lipopolysaccharide-induced shock, a monokine-mediated inflammatory reaction. A single injection of 0.5-1/~g of recombinant murine IL-10 reproducibly protected BALB/c mice from a lethal intraperitoneal injection of endotoxin. This result was obtained whether the I1:10 was administered concurrently with, or 30 min after the injection of endotoxin. The protective effect of IL-10 was reversed by prior injection of neutralizing anti-I1:10 antibodies, and correlated with a substantial decrease in endotoxin-induced TNF-ot release. These data implicate IL-10 as a candidate for treatment of bacterial sepsis, and more generally as an effective antiinflammatory reagent.

We have previously shown that continuous administration of anti-interleukin 10 (anti-IL-10) antibodies (Abs) to BALB/c mice modifies endogenous levels of autoantibodies, tumor necrosis factor alpha (TNF-alpha), and interferon gamma, three immune mediators known to affect the development of autoimmunity in "lupus-prone" New Zealand black/white (NZB/W)F1 mice. To explore the consequences of IL-10 neutralization in NZB/W F1 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 F1 mice as monitored either by overall survival, or by development of proteinuria, glomerulonephritis, or autoantibodies. Survival at 9 mo was increased from 10 to 80% in anti-IL-10-treated mice relative to Ig isotype-treated controls. This protection against autoimmunity appeared to be due to an anti-IL-10-induced upregulation of endogenous TNF-alpha, since anti-IL-10-protected NZB/W F1 mice rapidly developed autoimmunity when neutralizing anti-TNF-alpha Abs were introduced at 30 wk along with the anti-IL-10 treatment. Consistent with the protective role of anti-IL-10 treatment in these experiments, continuous administration of IL-10 from 4 until 38 wk of age accelerated the onset of autoimmunity in NZB/W F1 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 that IL-10 antagonists may be beneficial in the treatment of human systemic lupus erythematosus.

1 The e ects of the long lasting and potent PAF receptor antagonist UK74505 were assessed on the local and remote injuries following ischaemia and reperfusion (I/R) of the superior mesenteric artery (SMA) in rats.2 In a severe model of ischaemia (120 min) and reperfusion (120) injury, in addition to the local and remote increases in vascular permeability and neutrophil accumulation, there was signi®cant tissue haemorrhage, blood neutropenia, systemic hypotension and elevated local and systemic TNFa levels. 3 Post-ischaemic treatment with the selectin blocker fucoidin (10 mg kg 71 ) prevented neutrophil accumulation in tissue and, in consequence, all the local and systemic injuries following severe I/R. 4 Treatment with an optimal dose of UK74505 (1 mg kg 71 ) also reversed local and remote neutrophil accumulation, increases in vascular permeability and intestinal haemorrhage. UK74505 partially inhibited blood neutropenia and reperfusion-induced hypotension. 5 Interestingly, both fucoidin and UK74505 prevented the local, but not systemic, increases of TNF-a levels following severe I/R injury, demonstrating an important role of migrating cells for the local production of TNF-a. However, the results do not support a role for PAF as an intermediate molecule in the production of systemic TNF-a. 6 The bene®cial e ects of UK74505 and other PAF receptor antagonists in models of I/R injury in animals and the safety of UK74505 use in man warrant further investigations of the use of this drug as preventive measure for I/R injury in humans.

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