Administration of interleukin-2 (IL-2) results in increased plasma concentrations of IL-5 and eosinophilia in patients with cancer

Abstract

Peripheral eosinophilia is almost invariably observed during the course of interleukin-2 (IL-2) therapy and is frequently accompanied by the development of a capillary leak syndrome characterized by edema, weight gain, and oliguria. We studied five patients with advanced malignancy treated with IL-2. Eosinophilia was not present initially but developed in all patients late in the course of therapy, with counts ranging from 2,328/mm3 to 15,958/mm3. In all patients, there was a temporal relationship between the infusion of IL-2 and the appearance of elevated plasma concentrations of IL-5, a growth factor for eosinophils. Granulocyte-macrophage colony-stimulating factor was not detectable in plasma. IL-4 and gamma-interferon plasma levels were variably elevated. Plasma concentrations of major basic protein, a toxic eosinophil granule protein, began increasing before eosinophil counts increased. By the time of the third IL-2 infusion, high concentrations of major basic protein were present in all five patients (up to 5,600 ng/mL) and skin biopsies showed major basic protein deposition in the dermis. Four patients developed significant capillary leak syndrome and all of these patients showed markedly elevated major basic protein levels. The lowest peak plasma concentration of major basic protein (1,751 ng/mL) was observed in the one patient who did not develop edema and weight gain. These results suggest that IL-2 induces IL-5 leading to marked peripheral eosinophilia and extravascular eosinophil degranulation. The release of toxic eosinophil products at extravascular sites and in the circulation may contribute to the pathogenesis of the capillary leak syndrome complicating IL-2 therapy.

Expression of interleukin‐5 by human bone marrow microvascular endothelial cells: implications for the regulation of eosinophilopoiesis in vivo

“…During the Th1 state, early haemopoietic progenitors may still differentiate into the eosinophilic lineage in response to locally secreted IL-5. Also during therapeutic IL-2 administration, eosinophilia does not occur at the beginning of the treatment (van Haelst-Pisani et al, 1991). Final eosinophilic maturation and increased egress of eosinophils from the bone marrow may require additional T-cell-derived cytokine stimulation which occurs mainly during a Th2-type response.…”

Priming of eosinophil and neutrophil migratory responses by interleukin 3 and interleukin 5

“…On the other hand, the higher sensitivity of eosinophils to IL-5-induced priming of migratory responses might in most instances make the effect of IL-5 selective for eosinophils. In previous studies the concentration of IL-5 has been measured in plasma from asthmatic patients (7), patients with episodic angioedema and eosinophilia (22), and cancer patients treated with interleukin 2 (31), and in all cases the concentrations of IL-5 were in the picomolar range. Studies on receptors for IL-5 have revealed the presence of high-affinity receptors on eosinophils but not on neutrophils (6,17,21).…”

Regulation of Interleukin‐2 Induced Interleukin‐5 and Interleukin‐13 Production in Human Peripheral Blood Mononuclear Cells

“…Exogenous IL-4, in contrast, up-regulated IL-5 and IL-13. As IL-5 and ¹ possibly ¹ IL-13 might be associated with some of the serious adverse effects of IL-2 immunotherapy [21], it appears that addition of IL-12 might relieve, and addition of IL-4 might enhance, these.…”

“…These animals were characterized by a decreased number of eosinophils, which was responsible for a reduced immunity against helminths [19,20]. IL-5 is also produced in vivo during IL-2 immunotherapy in patients with cancer [3,21], and thus might be responsible for some of the side-effects of IL-2 therapy, namely hypotension and prerenal failure, capillary leakage, and pulmonary and peripheral oedema.…”