The goal of this study is to define the role of macrophages in the regulation of erythropoiesis. Macrophages directly influence the growth and development of erythroid progenitors, both in vitro and in vivo. Using a unique model system developed in our laboratory, we have found that macrophage regulation of erythropoiesis is impaired in erythroleukemia. This regulation can be restored and the disease reversed by treatment with normal macrophages. The mechanism by which macrophages regulate normal and leukemic erythropoiesis has been investigated. We have found that there is a regulatory network operative in vivo involving macrophages and erythroid progenitors (CFU-E), and potent positive and negative regulatory mediators. Macrophages produce a factor that greatly reduces in vivo CFU-E levels. This effect of macrophages is reversed by an erythroid stimulatory activity, related to but distinct from erythropoietin, induced by anemic stress and whose activity in vivo is controlled by macrophages.
The aims of this study are to isolate and characterize these erythroid regulatory activities; to determine their origins and mechanisms of action; to assess their roles in controlling normal and leukemic erythropoiesis; and to determine the interactions between hematopoietic controls and immune functions known to be involved in spontaneous and induced regression of erythroleukemia, in reversal of the disease. These findings reveal a novel and significant in vivo regulatory circuit for the erythroid compartment, responsive to external stimuli and tightly controlled by positive and negative mediators. The systems we have developed uniquely allow analysis of this regulatory axis, both in vitro and in vivo. Our studies offer the possibility of gaining a greater understanding of erythropoiesis and ultimately a potential for use of this knowledge in the therapy of hematopoietic disorders.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA033188-05
Application #
3171127
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1983-05-01
Project End
1989-11-30
Budget Start
1987-12-01
Budget End
1988-11-30
Support Year
5
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Amc Cancer Research Center
Department
Type
DUNS #
City
Denver
State
CO
Country
United States
Zip Code
80214
Pourbohloul, S C; Thurlow, S M; Furmanski, P et al. (1992) Induction of permanent regression of Friend virus (FV) leukemia by adoptive transfer of T helper and not T cytotoxic cells. Leuk Res 16:881-7
Chang, M J; Pourbohloul, S C; Yu, W D et al. (1992) Differential effect in vitro of tumor necrosis factor-alpha (TNF) on normal and virus-infected erythroid progenitors from Friend virus (FVA)-infected mice. Exp Hematol 20:1271-7
Braunschweiger, P G; Jones, S A; Johnson, C S et al. (1991) Potentiation of mitomycin C and porfiromycin antitumor activity in solid tumor models by recombinant human interleukin 1 alpha. Cancer Res 51:5454-60
Johnson, C S; Pourbohloul, S C; Furmanski, P (1991) Negative regulators of in vivo erythropoiesis: interaction of IL-1 alpha and TNF-alpha and the lack of a strict requirement for T or NK cells for their activity. Exp Hematol 19:101-5
Johnson, C S; Chang, M J; Braunschweiger, P G et al. (1991) Acute hemorrhagic necrosis of tumors induced by interleukin-1 alpha: effects independent of tumor necrosis factor. J Natl Cancer Inst 83:842-8
Furmanski, P; Johnson, C S (1990) Macrophage control of normal and leukemic erythropoiesis: identification of the macrophage-derived erythroid suppressing activity as interleukin-1 and the mediator of its in vivo action as tumor necrosis factor. Blood 75:2328-34
Braunschweiger, P G; Johnson, C S; Kumar, N et al. (1990) The effect of adrenalectomy and dexamethasone on interleukin-1 alpha induced responses in RIF-1 tumours. Br J Cancer 61:9-13
Johnson, C S; Braunschweiger, P G; Furmanski, P (1990) In vivo effects of recombinant human and murine interleukin-1 alpha (IL-1 alpha) on murine hematopoiesis. In Vivo 4:93-6
Furmanski, P; Li, Z P (1990) Multiple forms of lactoferrin in normal and leukemic human granulocytes. Exp Hematol 18:932-5
Johnson, C S; Cook, C A; Furmanski, P (1990) In vivo suppression of erythropoiesis by tumor necrosis factor-alpha (TNF-alpha): reversal with exogenous erythropoietin (EPO). Exp Hematol 18:109-13

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