Lymphokine activated killer (LAK) cell-mediated endothelial injury: a mechanism for capillary leak syndrome in patients treated with LAK cells and interleukin-2.
We have investigated the possible etiology of a severe clinical syndrome seen in cancer patients treated with a new form of cancer-specific therapy, referred to as adoptive immunotherapy. This syndrome, apparently characterized by diffuse capillary injury, results in the leakage of intravascular fluid into interstitial tissues, with consequent organ dysfunction that limits the applicability of this form of therapy. We have demonstrated, using an in vitro model of cultured human endothelial cell injury, that LAK cells--lymphocytes stimulated in vitro by IL-2--appear to be potent mediators of endothelial injury. This LAK cell-mediated endothelial cytotoxicity is both time and dose dependent and is not manifested by freshly isolated human lymphocytes or lymphocytes cultured for up to 7 days in the absence of IL-2. In contrast, significant LAK cell-mediated damage to human endothelial cells is observed in lymphocytes cultured for as little as 24 hr in media containing IL-2 and is still found in 14-day-old LAK cells. LAK cells appear to be far more potent than maximally stimulated PMNs in their cytolytic activity against endothelium. In contrast, no damage to cultured endothelial cells is provoked by very large doses of IL-2 alone. Levels of IL-2 that are 3-5 times greater than peak blood IL-2 levels, transiently present in patients following bolus IL-2 injections, fail completely to produce HEC cytotoxicity even during prolonged incubation. The mechanism by which LAK cells kill their targets appears to be analogous to that previously described for related cytolytic T lymphocytes and NK cells.(ABSTRACT TRUNCATED AT 250 WORDS)
D002196:Capillaries / Q000503:physiopathology*; D002460:Cell Line; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007116:Immunization, Passive / Q000009:adverse effects*; D007376:Interleukin-2 / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000637:transplantation; D008213:Lymphocyte Activation; D013577:Syndrome
D007376:Interleukin-2