Effects of recombinant dimeric TNF receptor on human inflammatory responses following intravenous endotoxin administration.
Effects of dimeric TNF receptor (p80) Fc (TNFR:Fc) on acute phase responses were evaluated in 18 volunteers given endotoxin (4 ng/kg i.v.). Subjects were randomized to receive either placebo (n = 6), low dose TNFR:Fc (10 mg/m2 i.v., n = 6), or high dose TNFR:Fc (60 mg/m2 i.v., n = 6). TNFR:Fc blocked plasma TNF bioactivity (p = 0.001) and increased, in a dose-ordered fashion, TNF immunoactivity (p < 0.001). TNFR:Fc decreased secondary cytokine levels including IL-1 beta (p = 0.007), IL-8 (p < 0.001), IL-1 receptor antagonist (p < 0.001), granulocyte-CSF (p = 0.03), and growth regulated peptide-alpha (p = 0.001) but not macrophage inflammatory protein-1 alpha or IL-10. Low dose, but not high dose, TNFR:Fc blunted or delayed the release of epinephrine and cortisol (p < or = 0.026). Despite the absence of plasma TNF bioactivity, high dose TNFR:Fc was less immunosuppressive than low dose TNFR:Fc as measured by cytokine and stress hormone responses. Endotoxin-related symptoms were not altered by TNFR:Fc and the febrile response was delayed but not diminished (p = 0.004). Increases in cardiac index (72 +/- 19%) and heart rate (60 +/- 10%) and decreases in systemic vascular resistance index (47 +/- 7%) were unaltered by TNFR:Fc. These data suggest that the inflammatory response to endotoxin can escape from high levels of circulating TNF-blocking activity and redundant pathways, independent of circulating TNF, can sustain inflammation and clinical responses caused by acute endotoxemia.
Suffredini
A F
AF
Critical Care Medicine Department, Warren G. Magnuson Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
Reda
D
D
Banks
S M
SM
Tropea
M
M
Agosti
J M
JM
Miller
R
R
D000818:Animals; D004731:Endotoxins / Q000009:adverse effects; D000068800:Etanercept; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology*; D007167:Immunotherapy; D007249:Inflammation / Q000209:etiology / Q000276:immunology / Q000628:therapy*; D007275:Injections, Intravenous; D008297:Male; D051379:Mice; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology*; D011994:Recombinant Proteins / Q000276:immunology
D004731:Endotoxins; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D011994:Recombinant Proteins; D000068800:Etanercept