Interleukin-2 Induced Systemic Toxicity: Induction of Mediators and Immunopharmacologic Intervention

Abstract

Interleukin-2 has been tested as an anti-cancer agent, either alone or in combination with immune cells, but severe dose limiting adverse toxic effects have been observed. Because the pathogenesis of the toxicity has remained uncharacterized, it has not been possible to determine whether the therapeutic and the toxic events could be separated. We have examined immunopharmacologic regulation of IL2 induced mediator induction and toxicity syndrome and have compared this data with our earlier information on IL2 enhancement of immune function in murine systems. The results of this study have shown that treatment with recombinant human interleukin-2 induced increased cellular TNF activity in lymphoid organs and this activity was abrogated by an anti-TNF antibody. Additionally, continuous daily treatment with interleukin-2 also induced increases in serum corticosterone but no detectable increases in serum IL1 or TNF. The increases in serum corticosterone occurred later in the treatment process and coincided with histopathologic changes in the adrenal glands and other tissues. Animals that died as a result of IL2 treatment had ascites and hydrothorax. Histopathologic changes were noted in the lungs, liver, adrenals, kidneys, gastrointestinal tract, heart and lymphoid organs. Cyclophosphamide, dexamethasone and anti-ASGM1 antibody were most effective in increasing survival and inhibiting immune enhancement but differentially effective in inhibiting TNF induction (or in certain cases gamma interferon induction), decreasing ascites or hydrothorax or affecting lymphoid proliferation in the lungs and spleen. Cyclosporin A and azathioprine were not as effective in enhancing survival and had differential effects on the other parameters. Possible mechanisms of both therapeutic and toxic events are discussed.

Improved IL-2 immunotherapy by selective stimulation of IL-2 receptors on lymphocytes and endothelial cells

“…According to the literature, VLS is believed to be caused by the release of proinflammatory cytokines from IL-2-activated NK cells (11,(15)(16)(17)(18)(19)(20). Instead, we show here that IL-2-induced pulmonary edema resulted from direct binding of IL-2 to lung endothelial cells, which expressed low to intermediate levels of functional αβγ IL-2Rs.…”

The Impact of Escitalopram on IL-2-Induced Neuroendocrine, Immune, and Behavioral Changes in Patients with Malignant Melanoma: Preliminary Findings

“…First, in response to IL-2 administration, over time, there appears to be an enhancement of ACTH response. This increasing ACTH secretion is congruent with previous preclinical and clinical studies showing that IL-2 administration is associated with activation of stress-responsive neuroendocrine pathways [corticotropin releasing hormone (CRH) and HPA axis] (Butler et al, 1989;Denicoff et al, 1987;Hanisch et al, 1994;Karanth and McCann, 1991;Katahira et al, 1998;Raab et al, 1999;Raber et al, 1995;Spina et al, 1994). We postulate that this enhanced ACTH response may be related to IL-2-induced dysregulation of glucocorticoid receptor function at the level of the pituitary, hypothalamus, and/or hippocampus (Raison and Miller, 2003a) and possibly due to interactions between glucocorticoid receptors and innate immune signaling pathways and/or activation of T-cell responses involving DNA binding of nuclear factor of activated T cells and activation protein-1.…”

“…As discussed above, activation of stress-responsive neuroendocrine pathways (CRH and HPA) likely contributed, given that ACTH plasma concentrations had a significant association with magnitude of HAM-D score. The release of proinflammatory cytokines implicated in mood regulation, including IL-6 and TNF-alpha (Butler et al, 1989;Raab et al, 1999;Saraya and Balkwill, 1993), during IL-2 therapy likely also contributed to the induction of depressive symptoms. Alterations in metabolism of certain monoamines (eg, serotonin, dopamine, acetylcholine) or receptor function (eg, NMDA) might also have been plausibly involved in IL-2's induction of depressive symptoms (Anisman and Merali, 1999;Lacosta et al, 2000).…”

Targeting the Immune System in Cancer

“…Effective anti-tumor response in conjunction with IL-2 warranted the use of high doses of IL-2. Although this approach showed promising clinical response in some patients, it was associated with toxic side effects which were probably mediated by the induction of other cytokines such as TNF [78] and factors such as nitric oxide [79]. Severe side effects of malaise, nausea, hypotension, fluid retention and organ dysfunction resulted in the admission of a large proportion of the patient in the Intensive Care Unit [80].…”