ABSTRACT
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.
Subject(s)
Carrier Proteins/adverse effects , Pseudomonas Infections/therapy , Receptors, Tumor Necrosis Factor , Shock, Septic/therapy , Sialoglycoproteins/adverse effects , Animals , Bacteremia/blood , Carrier Proteins/chemistry , Carrier Proteins/therapeutic use , Colony Count, Microbial , Cyclophosphamide/pharmacology , Drug Therapy, Combination , Endotoxins/blood , Humans , Immunosuppressive Agents/pharmacology , Immunotherapy/adverse effects , Interleukin 1 Receptor Antagonist Protein , Interleukin-1 , Neutropenia/chemically induced , Polyethylene Glycols/chemistry , Pseudomonas Infections/pathology , Pseudomonas aeruginosa/growth & development , Rats , Receptors, Tumor Necrosis Factor, Type I , Recombinant Proteins/adverse effects , Shock, Septic/pathology , Sialoglycoproteins/therapeutic use , Tumor Necrosis Factor Decoy Receptors , Tumor Necrosis Factor-alpha/analysisABSTRACT
A chimeric protein consisting of the N-terminal domain of lipopolysaccharide-binding protein and the C-terminal domain of bactericidal/permeability-increasing protein demonstrated a dose-dependent survival benefit (P = 0.001) and reduced endotoxin levels (P < 0.01) in neutropenic rats with Pseudomonas aeruginosa sepsis. This lipopolysaccharide-binding protein-bactericidal/ permeability-increasing peptide has favorable pharmacokinetics and antiendotoxin properties which may be of value for human sepsis.
