Passive immunization against tumor necrosis factor inhibits interleukin-2-induced microvascular alterations and reduces toxicity.
BACKGROUND
Antineoplastic therapy with interleukin-2 (IL-2) has been limited by dose-dependent systemic toxicities. Previous studies suggest that the hemodynamic instability and "vascular leak syndrome" that develop immediately after IL-2 administration occur secondary to neutrophil-mediated events in the microcirculation. Because IL-2 has limited direct effects on neutrophils and acutely induces the production of tumor necrosis factor-alpha (TNF), we hypothesized that the acute microvascular alterations and hemodynamic instability induced by IL-2 were mediated by TNF.


METHODS
The cremaster muscles of anesthetized rats were prepared for intravital microscopy. All animals were injected with fluorescein isothiocyanate conjugated to bovine serum albumin, and relative interstitial fluorescence was quantitated as an index of macromolecular leakage. Vital signs, leukocyte-endothelial interactions, and interstitial fluorescence were quantitated every 30 minutes for 2 hours after intravenous injections of IL-2, TNF, and IL-2 with polyclonal antibody to TNF.


RESULTS
Both IL-2 and TNF acutely induced hypotension, tachycardia, increased macromolecular leakage, and increased leukocyte-endothelial adherence. Polyclonal antibody to TNF effectively inhibited IL-2-induced leukocyte-endothelial adherence, macromolecular leakage, and hypotension.


CONCLUSIONS
These data suggest that the acute microvascular alterations and hypotension induced by IL-2 are mediated by TNF.
Edwards
M J
MJ
Department of Surgery, University of Louisville School of Medicine, KY 40292.
Abney
D L
DL
Heniford
B T
BT
Miller
F N
FN
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D007116:Immunization, Passive; D007275:Injections, Intravenous; D007376:Interleukin-2 / Q000009:adverse effects / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007962:Leukocytes / Q000187:drug effects; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D009132:Muscles / Q000098:blood supply*; D051381:Rats; D011919:Rats, Inbred Strains; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology*
D007376:Interleukin-2; D014409:Tumor Necrosis Factor-alpha