REGULATION OF MYELOID PROGENITOR CELL DIFFERENTIATION

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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.