Interleultin‐2 treatment‐associated eosinophilia is mediated by interleultin‐5 production

Abstract

During a trial using recombinant human interleukin-2 (rhIL-2) immunotherapy for acute myeloblastic leukaemia (AML) in remission, eosinophilia was observed in all patients. We used in-vitro clonogenic assays to investigate the mechanism of the eosinophilia in five patients. The mean eosinophil count increased from 0.05 x 10(9)/l before rhIL-2 to 0.98 x 10(9)/l within 48 h of stopping the infusion, and an exponential correlation between the pretreatment lymphocyte CD4:CD8 ratio and the maximum eosinophil count was observed. RhIL-2 did not stimulate eosinophil colony formation by normal bone marrow. However, serum collected from patients during rhIL-2 infusion was a potent stimulator of eosinophil colony forming units (CFU-Eo), but had no significant stimulatory effect on granulocyte-macrophage colony forming units (CFU-GM). The CFU-Eo stimulation by pre-treatment serum was 2.8-fold higher than control serum. Serum collected during treatment stimulated CFU-Eo 12 times more than control serum (P less than 0.05). By pre-incubating patient serum, collected during rhIL-2 treatment, with monoclonal antibodies to murine IL-5, or human granulocyte-macrophage colony stimulating factor (GM-CSF), a reduction of 80% and 38% respectively in eosinophil and GM colony production was found. The CFU-Eo stimulating effect of patient serum was in the range of the CFU-Eo stimulating effect of normal serum, after the addition of 5 u/ml of recombinant murine IL-5. The results suggest that eosinophilia was caused by IL-5 and GM-CSF production by rhIL-2 stimulated CD4 positive lymphocytes. The location on chromosomes 5 of the genes for IL-5, GM-CSF and IL-3 may be associated with regulation of expression, by a common mechanism, of all the factors known to be involved in eosinophil production. This mechanism may be activated by IL-2 stimulation. The separate location on chromosome 17 of the G-CSF gene may explain the ability of IL-2 to produce a distinct stimulus to eosinophil but not neutrophil production.

Non‐small‐cell lung cancer associated with excessive eosinophilia and secretion of interleukin‐5 as a paraneoplastic syndrome

“…In addition, patients receiving IL-2 biotherapy for malignancy frequently develop eosinophilia. IL-2 appears to induce the production of IL-5 by activated T-cells [9]. These studies support the hypothesis that IL-5 alone is sufficient to induce the full pathway of eosinophil production and differentiation, and has a specific stimulatory effect on eosinophils [4].…”

Eosinophils and Cancer – Mini Review

“…Although tumor-related eosinophilia was considered to be an epiphenomenon arising from the spontaneous elaboration of IL-5 from tumor cells, or overproduction of T cells during chemotherapy with IL-2 [19], there is evidence of eosinophil activation as a result of IL-2 anticancer therapy [20,21]. In some cases, tissue eosinophilia is considered to be a positive prognosis for head and neck cancers [22] and advanced bladder cancer [23].…”

Hematotoxicity of lnterleukin-2 in Man: Clinical Effects and Comparison of Various Treatment Regimens

“…The exact mechanisms how cytokines used in the pre sent clinical trials may modify human hemopoiesis are not fully understood; it has been hypothesized that the induc tion and secretion of secondary humoral mediators such as GM-CSF and interleukin-5 contribute strongly to the functional and proliferative modulation of human periph eral blood progenitor cells [66,67,73]. In various clinical studies using i.v.…”