Interleukin 1 (IL-1) and tumor necrosis factor (TNF) are key participants in the body's response to infection, inflammation and immunologic challenge. Recently, IL-1 and TNF have aroused great interest by their role in the regulation of hematopoiesis. IL-1 and TNF have been shown to be capable of inducing a number of accessory cells to produce colony stimulating factors which have allowed for the growth of granulocyte- macrophage, erythroid, megakaryocytic and mixed lineage colonies. In vivo, IL-1 and TNF have been shown to provide radioprotective effects when given to mice 20 hours prior to irradiation and to enhance granulocyte recovery in cyclophosphamide-treated mice. IL-1 has also been reported to synergize with other colony stimulating factors in stimulating the productive of primitive high proliferative potential colony forming cells. Therefore, IL-1, TNF and./or IL-1/TNF-induced products may have direct effects on very primitive colony forming cells which demonstrate a high frequency for replating. Preliminary studies performed by us have demonstrated that prior incubation of bone marrow cells with IL-1 or TNF protects early hematopoietic progenitor cells from the lethal effects of the chemotherapeutic agent 4-hydroperoxycyclophosphamide (4-HC). In this proposed study, we plan to determine the role of IL-1 and TNF in maintaining and protecting early hematopoietic colony forming cells from 4- HC. We will determine the optimum time for incubation with IL-1 and TNF and the optimum IL-1 and TNF dose. Because of the potential clinical implication of this early progenitor protection by IL-1 and TNF, we will also determine whether IL-1 and TNF have any effects on leukemic ells. IL- 1 and TNF may provide selective protection from chemotherapeutic agents for normal progenitor cells while rendering the leukemic cells responsive to chemotherapy. In addition, we will determine the mechanism by which IL-1 and TNF protect early hematopoietic cells. Whether they operate directly or indirectly through the production of other cytokines. Clinical studies using 4-HC purged marrow for autologous transplantation have reported delayed engraftment and leukemic relapse. Therefore, higher doses or combinations of chemotherapy may be required. Our proposed research should have major clinical significance by assessing the role of IL-1 and TNF in protecting stem cells responsible for engraftment following chemotherapy.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
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Hematology Subcommittee 2 (HEM)
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University of Florida
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