Potential hazards of combination immunotherapy in the treatment of experimental septic shock.

Using an actual infection model of Pseudomonas aeruginosa sepsis in neutropenic rats, the potential utility of a combination anticytokine approach for the treatment of sepsis was tested. A dimeric tumor necrosis factor binding protein (TNF-BP) consisting of two soluble recombinant human TNF type 1 receptors linked with polyethylene glycol was used with recombinant human interleukin-1 receptor antagonist (IL-1ra). Despite having levels of bacteremia and endotoxemia similar to the control group (survivors, 0/18), 30% of IL-1ra-treated animals survived (P < .05); 31% of TNF-BP-treated animals survived (P < .01). Unexpectedly, the combination of IL-1ra plus TNF-BP proved to be uniformly fatal (survivors, 0/20). Endotoxin (P < .0001) and bacteremia (P < .01) levels were >10-fold higher than levels in animals treated with IL-1ra alone, TNF-BP alone, or placebo. Disseminated microabscesses in major organs were found in animals treated with combination immunotherapy. Combination anticytokine therapy may exacerbate systemic infection and worsen outcome in experimental sepsis.

利用中性粒细胞减少大鼠的铜绿假单胞菌败血症实际感染模型，测试了联合抗细胞因子方法治疗败血症的潜在效用。使用了一种由两个与聚乙二醇连接的可溶性重组人1型肿瘤坏死因子受体组成的二聚体肿瘤坏死因子结合蛋白（TNF - BP），并与重组人白细胞介素 - 1受体拮抗剂（IL - 1ra）联合使用。尽管菌血症和内毒素血症水平与对照组相似（存活数为0/18），但接受IL - 1ra治疗的动物有30%存活（P <.05）；接受TNF - BP治疗的动物有31%存活（P <.01）。出乎意料的是，IL - 1ra加TNF - BP的组合被证明是一致致命的（存活数为0/20）。内毒素（P <.0001）和菌血症（P <.01）水平比单独使用IL - 1ra、单独使用TNF - BP或安慰剂治疗的动物高出10倍以上。在接受联合免疫治疗的动物主要器官中发现了播散性微脓肿。在实验性败血症中，联合抗细胞因子治疗可能会加剧全身感染并恶化结果。