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.

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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.

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Research in adoptive immunotherapy such as lymphokine-activated killer cell (LAK) generation requires a large number of mononuclear cells (MNCs). The original procedure for generation of LAK cells used a Ficoll-Hypaque (FH) purification of the MNCs collected by a blood separator to remove granulocytes, platelets, and red blood cells. Since the Fenwal CS 3000 blood separator produces MNCs with reduced granulocyte contamination, it is possible that FH purification could be replaced by a light centrifuge spin (LS) purification. We report on a study comparing the MNC recovery, platelet and red cell removal, purification time, in vitro LAK cytotoxicity, and phenotypic characterization of the lymphocytes, collected by FH purification vs. LS purification by using the CS 3000. Six donors were leukapheresed with the CS 3000 using a shortened LAK Cell procedure. Following an LS (3 minutes at 1,000 rpm), the MNC collection was divided into two equal aliquots, one aliquot purified by FH and the other aliquot purified by LS. Both aliquots were then washed, cultured for 5 days in IL-2, and harvested with the CS 3000. Our findings suggest the LS purification resulted in improved 1) postpurification MNC recovery (89% vs. 60%), 2) purification time (54 minutes vs. 129 minutes), and 3) LAK cell generation by phenotype. LS purification was similar to FH purification in 1) platelet removal and 2) in vitro LAK cytotoxicity. We found the LS superior to FH when considering efficiency, economics, simplicity, and LAK cell generation and comparable in platelet removal and in vitro LAK cytotoxicity.

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