title: Potential hazards of combination immunotherapy in the treatment of experimental septic shock.
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.
authors.affiliation: Brown University School of Medicine and Memorial Hospital, Providence, Rhode Island 02912, USA.
authors.forename: S M
authors.initials: SM
authors.lastname: Opal
authors.forename: A S
authors.initials: AS
authors.lastname: Cross
authors.forename: J W
authors.initials: JW
authors.lastname: Jhung
authors.forename: L D
authors.initials: LD
authors.lastname: Young
authors.forename: J E
authors.initials: JE
authors.lastname: Palardy
authors.forename: N A
authors.initials: NA
authors.lastname: Parejo
authors.forename: C
authors.initials: C
authors.lastname: Donsky
mesh_terms: D000818:Animals; D016470:Bacteremia / Q000097:blood; D002352:Carrier Proteins / Q000009:adverse effects* / Q000737:chemistry / Q000627:therapeutic use; D015169:Colony Count, Microbial; D003520:Cyclophosphamide / Q000494:pharmacology; D004359:Drug Therapy, Combination; D004731:Endotoxins / Q000097:blood; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007167:Immunotherapy / Q000009:adverse effects; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D009503:Neutropenia / Q000139:chemically induced; D011092:Polyethylene Glycols / Q000737:chemistry; D011552:Pseudomonas Infections / Q000473:pathology / Q000628:therapy*; D011550:Pseudomonas aeruginosa / Q000254:growth & development; D051381:Rats; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins / Q000009:adverse effects; D012772:Shock, Septic / Q000473:pathology / Q000628:therapy*; D012795:Sialoglycoproteins / Q000009:adverse effects* / Q000627:therapeutic use; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis
chemical_list: D002352:Carrier Proteins; D004731:Endotoxins; C507763:IL1RN protein, human; D007166:Immunosuppressive Agents; D053590:Interleukin 1 Receptor Antagonist Protein; D007375:Interleukin-1; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D011994:Recombinant Proteins; D012795:Sialoglycoproteins; D053319:Tumor Necrosis Factor Decoy Receptors; D014409:Tumor Necrosis Factor-alpha; C069521:recombinant human tumor necrosis factor-binding protein-1; D011092:Polyethylene Glycols; D003520:Cyclophosphamide