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Mechanism of Cultured Endothelial Injury Induced by Lymphokine-activated Killer Cells¹

Department of Medicine, Division of Hematology [D. K., G. M. V., H. S. J.], Immunobiology Research Center [A. C. O., F. H. B.], and Department of Laboratory Medicine and Pathology [J. G. W.], University of Minnesota, Minneapolis, Minnesota 55455

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.

¹ Supported in part by Grants HL 19725, HL 28935, HL 07062, DK 01387, and HL 33793.

² To whom requests for reprints should be addressed, at Box 480, University of Minnesota Hospital, Harvard Street at East River Road, Minneapolis, MN 55455.

Received 1/12/88. Revised 3/30/88. Revised 6/23/88. Accepted 7/ 5/88.

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