title: The activation of polymorphonuclear neutrophils and the complement system during immunotherapy with recombinant interleukin-2.
abstract: The toxicity due to interleukin-2 (IL-2) strongly resembles the clinical picture seen during septic shock. In septic shock activation of polymorphonuclear neutrophils (PMN) and the complement system contribute significantly to the pathophysiology of the condition. We therefore investigated whether similar events contributed to the toxicity observed with IL-2. Four patients received seven cycles of escalating dose IL-2 (18.0 to 72.0 X 10(6) IU m-2 day-1) and 16 were treated with 20 cycles of fixed dose IL-2 (12.0 or 18.0 X 10(6) IU m-2 day-1). Toxicity, as judged by hypotension (P = less than 0.005) and capillary leakage (fall in serum albumin 18.2 vs 4.0 gm l-1; P = less than 0.0005 and weight gain 4.0 vs 1.2 kg; P = less than 0.025) were worse with the esc. dose protocol. PMN became activated following IL-2 with mean peak elastase/alpha 1-antitrypsin (E alpha 1 A) and lactoferrin values of 212 (SEM = 37) and 534 (SEM = 92) ng ml-1 respectively occurring 6 h after the IL-2. Peak values for the esc. dose IL-2 group being generally higher than 500 ng ml-1. Activation of the complement cascade was evidenced by a dose dependent elevation of peak C3a values (fixed dose 9.1 (SEM = 0.6); esc. dose 25.7 (SEM = 6.33); P = less than 0.005) on day 5 of IL-2. There was a significant correlation between C3a levels and the degree of hypotention during the first 24 h after IL-2 (r = 0.91) and parameters of capillary leakage such as weight gain and fall in serum albumin (r = 0.71). These data suggest that activation of PMN initiates endothelial cell damage which subsequently leads to activation of the complement cascade. This latter system then contributes to the haemodynamic changes and capillary leakage seen in IL-2 treated patients.
authors.affiliation: Department of Medical Oncology, Free University Hospital, Amsterdam, Netherlands.
authors.forename: J W
authors.initials: JW
authors.lastname: Baars
authors.forename: C E
authors.initials: CE
authors.lastname: Hack
authors.forename: J
authors.initials: J
authors.lastname: Wagstaff
authors.forename: A J
authors.initials: AJ
authors.lastname: Eerenberg-Belmer
authors.forename: G J
authors.initials: GJ
authors.lastname: Wolbink
authors.forename: L G
authors.initials: LG
authors.lastname: Thijs
authors.forename: R J
authors.initials: RJ
authors.lastname: Strack van Schijndel
authors.forename: H L
authors.initials: HL
authors.lastname: van der Vall
authors.forename: H M
authors.initials: HM
authors.lastname: Pinedo
mesh_terms: D002292:Carcinoma, Renal Cell / Q000097:blood / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D003167:Complement Activation / Q000187:drug effects*; D015926:Complement C3a / Q000378:metabolism; D004334:Drug Administration Schedule; D004730:Endothelium, Vascular / Q000503:physiopathology; D005260:Female; D006098:Granulocytes / Q000502:physiology; D006801:Humans; D007167:Immunotherapy; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use*; D008175:Lung Neoplasms / Q000097:blood / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D008213:Lymphocyte Activation; D008297:Male; D008545:Melanoma / Q000097:blood / Q000276:immunology / Q000503:physiopathology / Q000628:therapy*; D008875:Middle Aged; D008954:Models, Biological; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000502:physiology
chemical_list: D007376:Interleukin-2; D011994:Recombinant Proteins; D015926:Complement C3a