In vivo hematopoietic effects of tumor necrosis factor-alpha in normal and
erythroleukemic mice: characterization and therapeutic applications
CS Johnson, MJ Chang and P Furmanski
Department of Cell Biology, AMC Cancer Research Center, Denver, CO 80214.
The effects of recombinant, macrophage-derived, murine tumor necrosis
factor-alpha (TNF-alpha) on hematopoiesis in vivo has been examined in
normal mice and in Friend virus (FV)-induced erythroleukemic mice.
Intravenous (IV) administration of a single dose of recombinant murine
TNF-alpha (10(5) U per mouse) significantly suppressed normal and leukemic
late-stage erythropoiesis as measured by numbers of mature erythroid colony
forming cells (CFU-E) in the bone marrow and spleen and by peripheral blood
reticulocyte counts. In normal animals, the immature erythroid (BFU-E),
macrophage (CFU-M), and granulocyte- macrophage (CFU-GM) compartments were
significantly stimulated by TNF- alpha in both the bone marrow and the
spleen. In the bone marrow of leukemic mice, the BFU-E, CFU-GM, and CFU-M
progenitor cell compartments were also stimulated by treatment with the
monokine. In the spleens of leukemic mice (the primary site of FV leukemia
cell accumulation), relative numbers of BFU-E and CFU-GM were increased by
TNF-alpha, while those of CFU-M were suppressed. TNF-alpha caused a rapid
decrease in the markedly elevated spleen weights of progressively leukemic
mice, and in multiple doses it caused complete clinical disease regression
in a significant percentage of leukemic animals. The combination of
TNF-alpha with interferon-gamma (IFN-gamma) increased the incidence of
leukemia regression, compared with TNF-alpha alone. These results show that
TNF-alpha exerts a suppressive influence on late-stage erythropoiesis in
vivo and suggest that this effect might be exploited in the treatment of
acute erythroleukemia, erythroid hyperplasias, and related diseases.
Volume 72,
Issue 6,
pp. 1875-1883,
12/01/1988
Copyright © 1988 by The American Society of Hematology
