Differential effects of sequential, simultaneous, and single agent interleukin-3 and granulocyte-macrophage colony-stimulating factor on megakaryocyte maturation and platelet response in primates.
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.
Stahl
C P
CP
Hematologic Diseases Branch, National Center for Infectious Diseases, Centers for Disease Control, Atlanta, GA 30333.
Winton
E F
EF
Monroe
M C
MC
Haff
E
E
Holman
R C
RC
Myers
L
L
Liehl
E
E
Evatt
B L
BL
D000818:Animals; D001792:Blood Platelets / Q000166:cytology*; D001854:Bone Marrow Cells; D004247:DNA / Q000378:metabolism; D004347:Drug Interactions; D005434:Flow Cytometry; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000494:pharmacology*; D006410:Hematopoiesis; D007377:Interleukin-3 / Q000008:administration & dosage / Q000494:pharmacology*; D008253:Macaca mulatta; D008533:Megakaryocytes / Q000166:cytology* / Q000378:metabolism; D010976:Platelet Count; D011003:Ploidies
D007377:Interleukin-3; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D004247:DNA