The proliferation of hematopoietic stem and progenitor cells in vivo is probably regulated by the colony stimulating factors (CSFs): interleukin-3 (IL-3) granulocyte-macrophage (GM)-CSF, granulocyte (G)-CSF, macrophage-CSF (CSF-1) and lactoferrin (LF). We will assess the production and action of CFSs.
The aims are to: 1) Investigate actions in vivo of low dosages of endotoxin- free purified preparations of recombinant (r) murine IL-3, r murine GM-CSF, r human G-CSF and murine CSF-1 alone and in combination. Myelopoiesis will be evaluated in normal mice, mice pretreated with LF, mice recovering from treatment with cyclophosphamide or 5-fluorouracil, and mice infected with the polycythemia inducing strain of the Friend Virus Complex. Mice will be assessed for bone marrow, spleen and peripheral blood counts and differentials, hematopoietic progenitors (CFU-GM, mature and """"""""immature"""""""" BFU-E, CFU-GEMM, HPP-CFC) and stem(s) cells per femur and spleen, the cycling status of these cells, self-renewal (replating) capacity of S-cells, and serum concentrations of IL-3, GM-CSF, G-CSF, CSF-1, IL-1, interferon IFN)- gamma and -alpha, prostaglandin E (PGE), acidic isoferritins (AIF) and tumor necrosis factor (TNF). 2) Determine the influence in vitro of murine and human CSFs (IL-3, GM-CSF, G- CSF, CSF-1) and human LF alone and in combination on production and release of CSFs, IL-1, AIF, PGE, IFN-gamma, IFN- alpha, and TNF from murine or human monocytes-macrophages, T-lymphocytes or fibroblasts with and without serum. This will entail: a. assessing effects on populations and subpopulations of cells within a lineage using cells separated with antibodies to subpopulation lineage antigens, and also cells expressing different densities of major histocompatibility class II antigens, b. correlating receptor-binding, gene expression for IL-3, GM-CSF, G-CSF, CSF-1, IL-1 alpha, IL-1 beta and release of biologically active molecules, c. characterizing differences between LF isolated from PMN of normal donors and patients with Chronic Myelogenous Leukemia by biochemical (iron-binding, carbohydrate, structural) and functional (receptor binding and mononuclear cell gene expression and release of IL-1, GM-CSF or G-CSF) analysis. These studies should help to evaluate the relevance of CSFs and LF and how they regulate myelopoiesis.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37CA036464-09
Application #
3482350
Study Section
Special Emphasis Panel (NSS)
Project Start
1984-07-01
Project End
1995-06-30
Budget Start
1992-07-15
Budget End
1993-06-30
Support Year
9
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Type
Schools of Medicine
DUNS #
005436803
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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