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Interleukin-1 Receptor Antibody (IL-1rab) Protection and Treatment against Lethal Endotoxemia in Mice

https://doi.org/10.1006/jsre.1993.1050Get rights and content

Abstract

Interleukin-1 (IL-1) is a mediator of endotoxin shock and IL-1 receptor blockade has been shown to have therapeutic efficacy against endotoxic shock and sepsis in laboratory models. The current studies were designed to characterize the efficacy of a murine monoclonal IL-1 receptor antibody (IL-1rab) against endotoxin (LPS) lethality and to investigate whether combined anticytokine therapy using the IL-1rab and a highly specific polyclonal rabbit anti-mouse TNF antibody (TNF Ab) could provide additive or synergistic efficacy against LPS lethality in C57B1/6 female mice. A single intraperitoneal (ip) dose of IL-1rab, 0.1 or 0.2 mg, significantly reduced lethality from LPS, 30 to 40 mg/kg ip, compared to nonimmune IgG, 0.1 or 0.2 mg, in control mice (P2 < 0.05). Treatment with IL-1rab was effective when administered from 6 hr before to 1 hr after LPS. After LPS, circulating levels of IL-6 were significantly lower in IL-1rab-treated mice [IL-6 (ng/ml) 2 h after LPS: IgG, 100 ± 25, IL-1rab, 41 ± 8; 4 h after LPS: IgG, 46 ± 13, IL-1rab, 8 ± 1; P2 < 0.05 and 0.03, respectively]. Northern blot analysis showed that IL-1rab markedly lowered IL-6 gene expression after LPS. Combined treatment with IL-1rab and TNF Ab did not result in any improvement in survival after LPS compared to either agent alone. These results indicate that an IL-1 receptor antibody has therapeutic efficacy against LPS and significantly decreases IL-6 production. Combined anticytokine treatment (against IL-1 and TNF) of endotoxic or septic shock does not appear justified on the basis of these results.

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    Citation Excerpt :

    Another approach to blocking the deleterious effects of IL-1 investigated in animal models utilized a neutralizing rat monoclonal antibody to the type 1 mouse IL-1 receptor. In these experiments, McNamara et al41 gave mice an intraperitoneal injection of IL-1 receptor antibody (IL-1rab; 0.02, 0.05, 0.1, or 0.2 mg) or IgG control 6 hours before a lethal intraperitoneal injection of LPS. Mice receiving 0.1 or 0.2 mg had significantly improved survival compared with IgG controls; mortality rates were 16, 0, and 100 percent, respectively.

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