Induction of circulating tumor necrosis factor (TNFα) as the mechanism for the febrile response to interleukin-2 (IL-2) in cancer patients

Abstract

Fever is frequently observed in cancer patients treated with high-dose recombinant human interleukin-2 (rIL-2). The preincubation of rIL-2 with polymyxin B, an antibiotic that inhibits the biologic effects of endotoxins, did not diminish the pyrogenicity of IL-2 in New Zealand rabbits, indicating that IL-2-induced fever is not due to contaminating endotoxins. In contrast to interleukin-1 (IL-1), tumor necrosis factor (TNF), and interferon alpha, which cause fever through their effects on arachidonic acid metabolism in the hypothalamus, IL-2 was unable to induce prostaglandin E2 synthesis in hypothalamic cells or fibroblasts in vitro, suggesting that IL-2 is not intrinsically pyrogenic. To determine if IL-2-induced fever is mediated indirectly through the generation of pyrogenic cytokines, culture supernatants from IL-2-stimulated human peripheral blood mononuclear cells were screened for the presence of pyrogens by direct injection into rabbits and by measuring the amounts of IL-1 alpha, IL-1 beta, and TNF alpha by specific radioimmunoassays (RIA). All three cytokines were readily detected by RIA in these supernatants, which in turn caused fever when injected into rabbits. Furthermore, in six of six cancer patients treated with rIL-2, elevated levels of TNF alpha were detected in the plasma by RIA 2 hr after IL-2 administration. Plasma TNF levels increased from pretreatment values of 14 +/- 7 to 765 +/- 150 pg/ml 2 hr after an IL-2 injection. These results strongly implicate IL-2-induced pyrogenic cytokines, in particular TNF alpha, as a major cause of the fever and possibly other aspects of the acute-phase response associated with IL-2 therapy.

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

“…In vitro, PMN can be activated by several agonists including cytokines such as TNF, GM-CSF and IL-8 as well as activation products of the complement system and in particular C5a (Slotman et al, 1986;Matsushima et al, 1989;Balkwill & Burke, 1989;Mantovani & Dejani, 1989;Tonnesen et al, 1984;Jacobs et al, 1980). These cytokines have been shown to be generated in vivo following IL-2 administration (Ward & Marks, 1989;Chong et al, 1989;Gemlo et al, 1988;Mier et al, 1988;Oppenheim, 1983). A recently published study by Mier and colleagues (Mier et al, 1990) showed that peak TNF levels occurred 2 h after IL-2 administration.…”

High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014

“…Although the specific molecular and cellular mechanisms of IL-2-mediated response and toxicity are not completely defined, IL-2 is known to result in a cascade of cytokines released at supraphysiologic levels in the body from IL-2-activated cells. This can result in a well-described capillary leak syndrome and eventual end-organ dysfunction [15][16][17][18][19][20][21][22][23][24][25][26][27]. The hallmarks of this "cytokine storm", are remarkably similar to the shock syndrome associated with bacterial septicemia, and include: sustained hypotension, tachycardia and increased vascular permeability.…”

“…Early animal and human studies suggested a dose-response effect on both efficacy and toxicity [15][16][17]. Thus most of the early literature described alternative methods of managing these patients than those used for sepsis, as the desirable therapeutic effects were thought to be linked to the toxicity (5)(6)(7)(8)(24)(25)(26)(27) and the inciting factor (IL-2 administration) was within the physician's control.…”

“…In the 1980's and 1990's, clinical trials evaluating the efficacy of HD IL-2 yielded a great deal of information on the physiologic effects of exogenous, HD recombinant IL-2 administration in humans [15][16][17][18][19][20][21][22][23][24][25][26][27]. Early clinical studies employed IL-2 often in combination with adoptively transferred lymphocytes referred to as Lymphokine Activated Killer (LAK) cells.…”

Interleukin 2-induced increase of vascular permeability without decrease of the intravascular albumin pool

“…However, the exact mechanisms by which IL-2 mediates the increase in vascular permeability are largely unknown. Some authors have demonstrated a direct effect of IL-2 in vitro on vascular permeability (Fairman et al, 1987;Downie et al, 1992), whereas others have suggested that IL-2 exerts this effect by induction of various cytokines (Mier et al. 1988;Fraker et al, 1989;Edwards et al, 1992) such as tumour necrosis factor alpha (TNF-m) ['5I]uptake by the thyroid gland.…”