Neutrophil activation, vascular leak toxicity, and cytolysis during interleukin-2 infusion in human cancer.
BACKGROUND
Recombinant interleukin-2 (rIL-2) therapy for advanced malignancy is usually associated with a vascular leak syndrome (VLS) similar to that seen in severe sepsis. We investigated the possibility that the IL-2-induced VLS may be associated with the presence of circulating activated polymorphonuclear (PMN) leukocytes as occurs in sepsis syndrome.


METHODS
Estimation of phenotypic (CD11B/CD18) and functional (H2O2, HOCl) up-regulation of circulating neutrophil activity was made by fluorescence-activated cell sorter analysis and ultraviolet spectrophotometry. Associated systemic cytokine enhancement tumor necrosis factor-alpha by enzyme-linked immunosorbent assay for bioactivity and parallel estimation of clinical evidence of vascular leak syndrome were also studied in human subjects with advanced cancer receiving therapeutic doses of rIL-2.


RESULTS
The present studies confirm previous reports that tumor necrosis factor-alpha is released into the circulation during infusional therapy with rIL-2. In addition, we have found that this is accompanied by both phenotypic (up-regulation of CD11b/CD18 adhesion receptor expression) and functional (hydrogen peroxide and hypochlorous acid production) evidence of potent PMN activation. Furthermore, patients showing disease response to treatment have significantly greater production of PMN oxidants.


CONCLUSIONS
These data suggest that the VLS seen during rIL-2 infusion in human beings may be attributable to PMN mechanisms similar to those invoked during severe sepsis. Consequently, this study may provide further insights into the mechanism of rIL-2's therapeutic action in advanced malignant disease.
Carey
P D
PD
University Department of Surgery, University of Wales College of Medicine, Heathpark, Cardiff, U.K.
Wakefield
C H
CH
Guillou
P J
PJ
D015703:Antigens, CD / Q000096:biosynthesis / Q000097:blood; D018821:CD18 Antigens / Q000096:biosynthesis; D002292:Carcinoma, Renal Cell / Q000628:therapy*; D005434:Flow Cytometry; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology*; D006684:HLA-DR Antigens / Q000096:biosynthesis; D006801:Humans; D006861:Hydrogen Peroxide / Q000097:blood; D016130:Immunophenotyping; D007262:Infusions, Intravenous; D007376:Interleukin-2 / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000628:therapy*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D016177:Macrophage-1 Antigen / Q000096:biosynthesis; D008545:Melanoma / Q000628:therapy*; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D015375:Receptors, Interleukin-2 / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D015854:Up-Regulation
D015703:Antigens, CD; D018821:CD18 Antigens; D006684:HLA-DR Antigens; D007376:Interleukin-2; D016177:Macrophage-1 Antigen; D015375:Receptors, Interleukin-2; D011994:Recombinant Proteins; D006861:Hydrogen Peroxide