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Interleukin-3 in vivo: kinetic of response of target cells
M Aglietta, F Sanavio, A Stacchini, S Morelli, L Fubini, A Severino, P Pasquino, C Volta, S Bretti and S Tafuto
Dipartimento di Scienze Biomediche ed Oncologia Umana, Universita di
Torino, Italy.
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.
Volume 82,
Issue 7,
pp. 2054-2061,
10/01/1993
Copyright © 1993 by The American Society of Hematology
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