Interleukin-2-induced lung injury. The role of complement.

Abstract

Pulmonary edema and sepsislike syndrome are grave complications of interleukin-2 (IL-2) therapy. Recent animal studies have suggested IL-2-induced microvascular injury as the underlying mechanism. Since complement factors have been shown to mediate increased vascular permeability in diverse conditions that lead to pulmonary injury and recombinant human IL-2 is known to activate the complement system in patients undergoing IL-2 therapy, we hypothesized that complement factors play a pivotal role in the development of increased vascular permeability after IL-2 treatment. To test this hypothesis, we evaluated the capacity of recombinant soluble human complement receptor type 1 (sCR1, BRL 55730), a new highly specific complement inhibitor, to attenuate IL-2-induced lung injury in the rat. Recombinant human IL-2 (intravenously for 60 I nterleukin-2 (IL-2) is under investigation as an immunotherapeutic agent used in the treatment of advanced metastatic cancer.12 The clinical toxicity of the IL-2 regimen includes sepsislike syndrome and pulmonary edema secondary to increased vascular permeability.3'4 Although the pathophysiological processes leading to these side effects are still obscure, several mechanisms have been proposed. For example, recent in vitro data have suggested that tissue injury is mediated by lymphokine-activated killer cells activated in response to IL-2.56 However, several in vivo studies conducted in sheep7-9 and rats10 cast doubt on this possibility, since lung microvascular injury has been demonstrated as early as 2 to 6 hours after IL-2 infusion, a time interval insufficient for lymphokine-activated killer cell generation." Neutrophils, which are early-response inflammatory cells, have been recently implicated in the pulmonary response to acute IL-2 administration.10'12 In addition, increased vascular permeability could be consequent to the IL-2-induced production of several humoral inflammatory mediators such as interleukin-1,"3 tumor necrosis factor-a minutes) at 106 U per rat (n=4) elevated lung water content (37±6%, P<.05), myeloperoxidase activity (162±49%, P<.05), and serum thromboxane B2 (30+±1 pg/100 ,uL,P<.01) and had no effect on serum tumor necrosis factor-a. sCR-1 at 30 mg/kg (n=5), but not at 10 mg/kg (n=6), attenuated the elevation of lung water content (18±2%, P<.05) and myeloperoxidase activity (42±9%, P<.05) but failed to alter serum thromboxane B2 response to IL-2. These data suggest the involvement of complement in the pathogenesis of IL-2-induced pulmonary microvascular injury and point to the potential therapeutic capacity of complement inhibitors in combating this toxic effect of IL-2 therapy. (Circ Res. 1994;74:329-335.)

A phase II study of interferon‐α, interleukin‐2 and 5‐fluorouracil in advanced renal carcinoma: clinical data and laboratory evidence of protease activation

“…Those responding to IL-2 have a prolonged studies. It is possible that recombinant soluble human complement receptor type-1 [17], and the second, equivalent hypotension and IL-2 may offer a survival advantage to those patients who respond, as the small percentage of patients who lower complement activation in six patients receiving high-dose IL-2 with C1 esterase inhibitor when compared enter a complete remission on IL-2 are reported to have a long progression-free and overall survival [6]. It is possible that recombinant soluble human complement receptor type-1 [17], and the second, equivalent hypotension and IL-2 may offer a survival advantage to those patients who respond, as the small percentage of patients who lower complement activation in six patients receiving high-dose IL-2 with C1 esterase inhibitor when compared enter a complete remission on IL-2 are reported to have a long progression-free and overall survival [6].…”

Association between increased levels of IL‐2 and IL‐15 and outcome in patients with early acute respiratory distress syndrome

“…IL‐2, which belongs to proinflammatory cytokines, is implicated in T‐lymphocyte proliferation and differentiation, as well as in stimulating the production of a number of interleukins, interferons and tumour necrosis factors [10]. IL‐2 infusion to cancer patients has been shown to induce a dose‐dependent activation of the complement system that correlated with the development of microvascular lung injury and therefore ARDS [10,11]. In addition, IL‐2 is able to induce microvascular lung injury in animals [12].…”

Recombinant Soluble Human Complement Receptor Type 1 Inhibits Antisperm Antibody- and Neutrophil-Mediated Injury to Human Sperm1

“…The solubilized truncated extracellular form (200 kDa) of recombinant CR1 (sCR1) purified from the medium of Chinese hamster ovary cells transfected with CR1 cDNA has demonstrated efficacy in inhibiting both antibody-mediated and nonantibody-mediated C-dependent tissue injury in vivo. Recombinant sCR1 has been shown to ameliorate Cmediated organ injury by inhibiting the generation and subsequent deposition of C3b and C5b-9 on target cells and preventing the infiltration of neutrophils in experimental animal models of human disease such as graft rejection [30][31][32]; intestinal [331, pulmonary [34], myocardial [35,36], and skeletal [37] ischemia/reperfusion injury; autoimmune allergic encephalomyelitis [38]; and pulmonary edema and sepsis-like syndrome [39].…”