Mechanism of cultured endothelial injury induced by lymphokine-activated killer cells.
A new form of therapy of experimental tumors, utilizing lymphokine-activated killer (LAK) cells and high doses of interleukin 2, has recently been applied in the treatment of human neoplasms. Severe side effects, suggestive of a diffuse vascular injury of unknown etiology, have prevented a more widespread application of this form of therapy. We have investigated the etiology of this clinical capillary leak syndrome, using an in vitro model of endothelial injury. LAK cells, but not interleukin 2 itself, are cytotoxic to cultured human endothelial cells, and this cytotoxicity is time and dose dependent. This human endothelial cell cytotoxicity can be inhibited by depletion of extracellular Ca2+, inhibition of the effector cell microtubular system, and inhibitors of serine proteases, but is not inhibited in the presence of toxic oxygen radical scavengers. LAK cell-mediated endothelial cytotoxicity is far more potent than that exhibited by maximally stimulated polymorphonucleocytes. LAK cell-mediated injury of human endothelium may possibly be responsible for the capillary leak syndrome observed in patients treated with high doses of interleukin 2 and LAK cells.
Kotasek
D
D
Department of Medicine, University of Minnesota, Minneapolis 55455.
Vercellotti
G M
GM
Ochoa
A C
AC
Bach
F H
FH
White
J G
JG
Jacob
H S
HS
D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D004730:Endothelium, Vascular / Q000473:pathology*; D006801:Humans; D007116:Immunization, Passive / Q000009:adverse effects*; D007376:Interleukin-2 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008854:Microscopy, Electron; D012697:Serine Endopeptidases / Q000378:metabolism
D007376:Interleukin-2; D012697:Serine Endopeptidases; D002118:Calcium