title: Combination immunotherapy with soluble tumor necrosis factor receptors plus interleukin 1 receptor antagonist decreases sepsis mortality.
abstract: OBJECTIVE
  Inhibition of tumor necrosis factor (TNF) or interleukin 1 (IL-1) alone has not improved sepsis survival in human clinical trials; therefore, it has been suggested that blockade of both may be successful. We tested whether combination immunotherapy would improve survival in mice subjected to a lethal lipopolysaccharide (LPS) challenge or the sepsis model of cecal ligation and puncture.
  
  
  METHODS
  Mice were treated with the combination immunotherapy and challenged with either a lethal dose of lipopolysaccharide or a septic challenge induced by cecal ligation and puncture.
  
  
  METHODS
  University research laboratory.
  
  
  METHODS
  Adult, female Balb/c mice.
  
  
  METHODS
  Mice were treated with the combination of the IL-1 receptor antagonist plus a polyethylene glycol-linked dimer of the TNF soluble receptor.
  
  
  RESULTS
  LPS lethality was reduced in the treated mice with a decrease in biologically active TNF in the plasma and peritoneal fluid. In the cecal ligation and puncture (CLP) model of sepsis, this combination immunotherapy for 1 day decreased plasma and peritoneal levels of IL-6 and the murine chemokines KC and MIP-2. However, treatment did not result in a reduction in the hypothermia or peripheral blood alterations that occur after CLP, and the 1-day therapy did not result in an improvement in survival. In contrast, when combination immunotherapy was extended to 3 days there was a significant improvement in survival.
  
  
  CONCLUSIONS
  These data demonstrate that inhibition of both TNF and IL-1 will decrease the lethality of sepsis initiated by CLP if the combination immunotherapy is provided for a sufficient amount of time.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, MI, USA. remickd@umich.edu
authors.forename: D G
authors.initials: DG
authors.lastname: Remick
authors.forename: D R
authors.initials: DR
authors.lastname: Call
authors.forename: S J
authors.initials: SJ
authors.lastname: Ebong
authors.forename: D E
authors.initials: DE
authors.lastname: Newcomb
authors.forename: P
authors.initials: P
authors.lastname: Nybom
authors.forename: J A
authors.initials: JA
authors.lastname: Nemzek
authors.forename: G E
authors.initials: GE
authors.lastname: Bolgos
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000627:therapeutic use*; D001202:Ascitic Fluid / Q000737:chemistry; D002432:Cecum / Q000601:surgery; D054426:Chemokine CXCL2; D018925:Chemokines / Q000032:analysis / Q000097:blood; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004359:Drug Therapy, Combination; D004926:Escherichia coli; D004927:Escherichia coli Infections / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000401:mortality / Q000628:therapy*; D005260:Female; D007167:Immunotherapy / Q000379:methods*; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6 / Q000032:analysis / Q000097:blood; D008026:Ligation; D008070:Lipopolysaccharides; D051379:Mice; D008807:Mice, Inbred BALB C; D010949:Plasma / Q000737:chemistry; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology / Q000627:therapeutic use*; D047888:Receptors, Tumor Necrosis Factor, Type I; D018805:Sepsis / Q000276:immunology / Q000378:metabolism / Q000382:microbiology / Q000401:mortality / Q000628:therapy*; D012795:Sialoglycoproteins / Q000276:immunology / Q000627:therapeutic use*; D016019:Survival Analysis; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism
chemical_list: D015703:Antigens, CD; D054426:Chemokine CXCL2; D018925:Chemokines; C404915:Cxcl2 protein, mouse; C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D053590:Interleukin 1 Receptor Antagonist Protein; D015850:Interleukin-6; D008070:Lipopolysaccharides; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D012795:Sialoglycoproteins; D014409:Tumor Necrosis Factor-alpha