Interleukin-3 in vivo: kinetic of response of target cells

Abstract

Human recombinant interleukin-3 (IL-3; Sandoz AG, Basel, Switzerland) was administered for 7 days to patients with neoplastic disease and normal hematopoiesis. The purpose of the study was to assess IL-3 toxicity, to identify target cells, to define their kinetics of response at different dose levels, and to determine if IL-3 in vivo increased the sensitivity of bone marrow (BM) progenitors to the action of other hematopoietic growth factors. A total of 21 patients entered the study; the dosage ranged from 0.25 to 10 micrograms/kg/d. The effect on peripheral blood cells during treatment showed no significant changes in the number of platelets, erythrocytes, neutrophils, or lymphocytes (and their subsets). A mild monocytosis and basophilia occurred. Eosinopenia, present in the first hours of treatment, was followed by a dose-and time-dependent eosinophilia. IL-3 treatment affected BM cell proliferation by increasing the percentage of BM progenitors engaged in the S-phase of the cell cycle. The effect was dose dependent, with the various progenitors showing different degrees of sensitivity. The most sensitive progenitors were the megakaryocyte progenitors (colony-forming unit-megakaryocyte), then the erythroid progenitors (burst-forming unit-erythroid), and finally the granulo- monocyte progenitors (colony-forming unit-granulocyte-macrophage) whose proliferative activity was stimulated at the higher doses of IL-3. Only a slight increase in the proliferative activity of myeloblasts, promyelocytes, and myelocytes was observed, whereas the activity of erythroblasts was unchanged. The priming effect was such that BM progenitors, purified from patients treated with IL-3, produced more colonies in vitro in the presence of granulocyte colony-stimulating factor (G-CSF; granulocyte colonies), IL-5 (eosinophil colonies), and granulocyte-macrophage CSF (GM-CSF; predominantly eosinophil colonies). These data indicate that even in vivo IL-3 acts essentially as a primer for the action of other cytokines. Therefore, optimum stimulus of myelopoiesis will require either endogenous or exogenous late-acting cytokines such as G-CSF, erythropoietin, GM-CSF, and IL-6 for achieving fully mature cells in peripheral blood. If exogenous cytokines are used with IL-3, it is likely that G-CSF will yield more neutrophils, whereas GM-CSF may enhance eosinophils, monocytes, and neutrophils. Attention to the clinical relevance of each cell type will be necessary and should determine the selection of the combination of cytokines.

Leridistim, a Chimeric Dual G‐CSF and IL‐3 Receptor Agonist, Enhances Multilineage Hematopoietic Recovery in a Nonhuman Primate Model of Radiation‐Induced Myelosuppression: Effect of Schedule, Dose, and Route of Administration

“…route at the 200 μg/kg dose in a daily schedule compared favorably with the previously published effects of the structurally distinct, myelopoietin (SC‐68420), which stimulated hematopoiesis when administered s.c., in qd or bid schedules in the same model presented herein [18]. The probable mechanisms responsible for the stimulation observed with the abbreviated schedule remain in effect: the IL‐3 component may prime hematopoietic progenitor cells for subsequent stimulation by growth factors released within the radiation‐damaged marrow microenvironment [29–, 31], IL‐3 and G‐CSF can exert trophic and survival‐promoting effects on responsive progenitors within the post‐irradiation microenvironment [32–, 37], IL‐3 receptors are present on CD34 + cell subsets purified from human and rhesus marrow [24,, 38,, 39], and combined IL‐3 and G‐CSF are noted for their synergistic effects on myelopoiesis and megakaryocytopoiesis [26,, 30,, 31,, 40–, 42]. Leridistim binds with high affinity to both the IL‐3 and G‐CSF receptor complexes.…”

Inhibitory effect of interleukin 3 on early development of human B‐lymphopoiesis

“…Interleukin 3 (IL‐3) is a multipotent haematopoietic growth factor produced by activated T cells, monocytes/macrophages and stromal cells (Metcalf, 1989, 1993; Ogawa, 1994), and exerts its function through the IL‐3 receptor, consisting of a ligand‐binding α‐chain (IL‐3Rα) and a signal‐transducing β‐chain, the so‐called common β‐chain, which is also used by receptors for granulocyte‐macrophage colony‐stimulating factor or IL‐5. IL‐3 stimulates the proliferation and differentiation of haematopoietic cells of various lineages including neutrophil, eosinophil, basophil, megakaryocyte and erythroid lineages (Suda et al , 1985; Ihle, 1992; Aglietta et al , 1993). IL‐3 also affects the development of B cells but the effect seems complex.…”

Early suppressive effects of chemotherapy and cytokine treatment on committed versus primitive haemopoietic progenitors in patient bone marrow

“…Chemotherapy regimens have been shown to induce short-term as well as long-term suppressive or cytotoxic effects on bone marrow function (Betticher et al, 1993;Bhavnani et al, 1989;Cohen et al, 1982;Greenberger, 1991;Marsh, 1976;Mukai et al, 1992;Neben et al, 1993;Radford et al, 1990;Rice et al, 1992). Recent reports demonstrated that IL-3, GM-CSF and PIXY321 have stimulatory effects on bone marrow function (Aglietta et al, 1990(Aglietta et al, , 1993Albin et al, 1994;Broxmeyer et al, 1988Broxmeyer et al, , 1995Johnsen et al, 1994;Orazi et al, 1992;O'Reilly et al, 1990;Schmitz et al, 1994). In patients with normal haemopoiesis, IL-3, GM-CSF and PIXY321 administration promoted an increase in marrow cellularity in addition to an increase in blood cell counts (Johnsen et al, 1994;Vadhan-Raj, 1994).…”

“…In patients with normal haemopoiesis, IL-3, GM-CSF and PIXY321 administration promoted an increase in marrow cellularity in addition to an increase in blood cell counts (Johnsen et al, 1994;Vadhan-Raj, 1994). The percentage of committed progenitors in S phase of the cell cycle was also significantly elevated during administration of IL-3, GM-CSF or PIXY321 (Aglietta et al, 1990(Aglietta et al, , 1993Broxmeyer et al, 1995;Vadhan-Raj, 1994). After high-dose cyclophosphamide, IL-3 and GM-CSF promoted an earlier increase in marrow cellularity and a greater increase in the percentage of proliferating cells than was observed in patients treated with cyclophosphamidewithout cytokines (Orazi et al, 1992).…”