The activation of polymorphonuclear neutrophils and the complement system during immunotherapy with recombinant Interleukin-2

Abstract

Summary 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 106 IU m-2 day-') and 16 were treated with 20 cycles of fixed dose IL-2 (12.0 or 18.0 x 106 IU m-2 day-'). Toxicity, as judged by hypotension (P = <0.005) and capillary leakage (fall in serum albumin 18.2 vs 4.0 gm 1'; P = <0.0005 and weight gain 4.0 vs 1.2 kg; P = <0.025) were worse with the esc. dose protocol.PMN became activated following IL-2 with mean peak elastase/a,-antitrypsin (Ea,A) and lactoferrin values of 212 (SEM = 37) and 534 (SEM = 92) ng ml-' respectively occurring 6 h after the IL-2. Peak values for the esc. dose IL-2 group being generally higher than 500 ng ml-'. 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 = <0.005) on day 5 of IL-2.There was a significnt 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.

Taurine Prevents Interleukin-2-Induced Acute Lung Injury in Rats

“…The interaction between acti- Abdih/Kelly/Bouchier-Hayes/Barry/Kearns vated neutrophils and endothelial cells has been shown to play a significant role in the pathogenesis of the vascular leak syndrome [9,10]. Clinical studies support these findings with evidence of neutrophil activation and a direct correlation between activation and markers of vascular leakage, such as weight gain and fall in serum albumin [11].…”

“…The role of activated neutrophils in mediating the vascular leak syndrome has been demonstrated both experimentally and clinically after IL-2 therapy [9,11]. Activated neutrophils express increased amounts of adhesion molecules and adhere to the vascular endothelium [21,22].…”

Effect of recombinant human interleukin 2 on neutrophil adherence to endothelial cells in vitro

“…Within hours of systemic adminis-361 0360-3997/96/0800 0361509.50/0 (0 1996 Plenum Publishing Corlx~ration trations of high dose IL-2, the patients may develop a VLS very similar to that seen in patients in the early phases of septic shock (1)(2)(3)(4)(5)(6). Although the pathophysiological mechanisms of VLS induced by IL-2 are not understood well, considerable evidence indicates that increased vascular permeability is caused by endothelial cell activation and damage mediated via cytokines including IL-1, IL-6, IL-8, granulocyte-macrophage colony stimulating factor (GM-CSF), tumor necrosis factor-~ (TNF-~) and interferon-7 (IFN-7) (7-9), activated immune effector cells such as neutrophils and LAK cells, and activation of complement (10,11). Neutrophil adhesion to the vascular endothelial cells appears to be a critical step in the development of VLS (11)(12)(13).…”

A pilot study to evaluate the effects of C1 esterase inhibitor on the toxicity of high-dose interleukin 2

“…During IL-2 therapy the complement system becomes activated Moore et al, 1991;Vachino et al, 1991;Baars et al, 1992;Clayman et al, 1992). This activation is dose dependent (Thijs et al, 1990;Baars et al, 1992), occurs via several pathways including the classical route (Thijs et al, 1990;Moore et al, 1991;Vachino et al, 1991), and correlates with the degree of hypotension induced (Baars et al, 1992) and parameters of capillary leakage (Thijs et al, 1990;Baars et al, 1992). The classical route of complement activation is regulated by Cl esterase inhibitor (C1-INH).…”