This application will investigate the relationships between recombination growth factors and inhibitors in controlling myeloid progenitor cell proliferation the understanding of the interactive effects of these biomolecules is important to the ultimate clinical use of these factors for biotherapy. The interegulatory roles of recombinant murine and human growth factors G-CSF, GM-CSF, M-CSF (CSF1) Interleukin 3 and Interkeukin 1, and inhibitors, interferons alpha, beta and gamma Tumor Necrosis Factor (TNF) and prostaglandin E (PCE), in the control of murine and human hematopoietic progenitor cell proliferation will be investigated. A novel-PGE2 induced hematopoietic suppressor mechanism has been demonstrated intact animals which has broad implications to suppressed hematopoiesis in patients with Aplastic Anemia, Anemia of Chronic Disease, and Leukemia. The ability of growth factors to similarly induce such a mechanism, or protect and/or override this mechanism will be analyzed in intact animals and in in vitro cell cultures A soluble inhibitor derived from bone marrow and spleens of mice treated with PGE2 in vivo will be biochemically purified, sequenced, cloned, and its mechanism of action determined. The capacity of PGE2 or the purified protein which mediates its effect, to protect hematopoiesis, in animal models of lethal irradiation and chemotherapy, will be tested in normal animals and tumor hosts. The role of growth factors to potentiate survival will be investigated. The interrelationships between human accessory cell factors, notably CSFs, PGE, IFNs and TNF with respect to cell source, kinetics of release and effects upon Erythropoiesis and Myelopoiesis will be studied in vitro using purified accessory cell populations, high enriched progenitor cell populations, recombinant factors, radioimmunoassays for PGE2 and in situ hybridization techniques. The potential regulatory effects of TGF beta on human hematopoiesis will be investigated using in vitro clonal agar methods.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA033225-07
Application #
3171179
Study Section
Hematology Subcommittee 2 (HEM)
Project Start
1985-09-01
Project End
1993-07-31
Budget Start
1988-08-01
Budget End
1989-07-31
Support Year
7
Fiscal Year
1988
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Pelus, L M (1989) Modulation of myelopoiesis by prostaglandin E2: demonstration of a novel mechanism of action in vivo. Immunol Res 8:176-84
Ottmann, O G; Abboud, M; Welte, K et al. (1989) Stimulation of human hematopoietic progenitor cell proliferation and differentiation by recombinant human interleukin 3. Comparison and interactions with recombinant human granulocyte-macrophage and granulocyte colony-stimulating factors. Exp Hematol 17:191-7
Nocka, K H; Ottman, O G; Pelus, L M (1989) The role of marrow accessory cell populations in the augmentation of human erythroid progenitor cell (BFU-E) proliferation by prostaglandin E. Leuk Res 13:527-34
Pelus, L M (1989) Blockade of prostaglandin biosynthesis in intact mice dramatically augments the expansion of committed myeloid progenitor cells (colony-forming units-granulocyte, macrophage) after acute administration of recombinant human IL-1 alpha. J Immunol 143:4171-9
Nocka, K H; Pelus, L M (1988) Cell cycle specific effects of deferoxamine on human and murine hematopoietic progenitor cells. Cancer Res 48:3571-5
Pelus, L M; Vadhan-Raj, S (1988) Modulation of responsiveness of chronic myelogenous leukemia granulocyte-macrophage colony-forming cells to growth regulation following in vivo treatment with recombinant gamma-interferon. Am J Hematol 28:21-6
Gentile, P S; Pelus, L M (1988) In vivo modulation of myelopoiesis by prostaglandin E2. IV. Prostaglandin E2 induction of myelopoietic inhibitory activity. J Immunol 141:2714-20
Pelus, L M; Ottmann, O G; Nocka, K H (1988) Synergistic inhibition of human marrow granulocyte-macrophage progenitor cells by prostaglandin E and recombinant interferon-alpha, -beta, and -gamma and an effect mediated by tumor necrosis factor. J Immunol 140:479-84
Pelus, L M; Levi, E; Welte, K (1988) The response of human marrow colony-forming units-granulocyte and macrophage to inhibition by prostaglandin E and acidic isoferritins is associated with expression of MHC class II antigens and requires the participation of a CD8+ T lymphokine. J Immunol 141:1658-64
Ottmann, O G; Pelus, L M (1988) Differential proliferative effects of transforming growth factor-beta on human hematopoietic progenitor cells. J Immunol 140:2661-5

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