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Differential effects of sequential, simultaneous, and single agent
interleukin-3 and granulocyte-macrophage colony-stimulating factor on
megakaryocyte maturation and platelet response in primates
CP Stahl, EF Winton, MC Monroe, E Haff, RC Holman, L Myers, E Liehl and BL Evatt
Hematologic Diseases Branch, National Center for Infectious Diseases,
Centers for Disease Control, Atlanta, GA 30333.
Recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF)
following interleukin-3 (IL-3) priming has been shown to increase
thrombopoiesis. To elucidate the comparative abilities of IL-3 and GM- CSF
in influencing megakaryocyte development in vivo, serial bone marrow
analyses were performed on rhesus monkeys treated with 5 micrograms/kg/d of
IL-3 and 5 micrograms/kg/d of GM-CSF sequentially for 4 days each,
simultaneously for 8 days, and as single agents for 8 days. Platelet counts
maximally increased to a mean of 7.5 x 10(5)/microL (n = 3) on days 11
through 12 in monkeys treated with sequential IL-3/GM-CSF. In contrast,
neither IL-3 alone nor simultaneously administered IL-3/GM-CSF elicited
increases in thrombopoiesis between days 3 and 15. GM-CSF elicited a
variable platelet response. Megakaryocyte ploidy distributions were
significantly (P < .001) shifted between days 7 and 10 in monkeys
treated sequentially and between days 3 and 15 in monkeys treated with
combined IL-3/GM-CSF and with GM-CSF alone but not in monkeys treated with
IL-3 alone. The changes in mean DNA content and megakaryocyte size, as
determined by digital image analysis, were larger in monkeys treated with
sequential IL-3/GM-CSF and with GM-CSF alone than in simultaneously treated
monkeys. In addition, sequentially but not simultaneously treated monkeys
showed increased numbers of megakaryocytes on bone marrow biopsy. We
conclude that administration of IL-3 followed by GM-CSF treatment increases
thrombopoiesis by sequentially increasing megakaryocyte numbers and
maturation and that these effects are diminished by simultaneous
administration of the two cytokines.
Volume 80,
Issue 10,
pp. 2479-2485,
11/15/1992
Copyright © 1992 by The American Society of Hematology
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