THE ROLE OF T LYMPHOCYTE FACTORS IN HEMOPOIESIS

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Inflammation is a complex host response that involves several biochemical pathways and all hemopoietic elements. T lymphocytes play an integral role in inflammatory responses by secreting soluble protein factors, lymphokines, that can regulate both the immunospecific and generalized aspects of the response. The first cells to arrive at a site of inflammation are neutrophilic granulocytes; macrophages usually appear several hours after granulocytes. Cloned T lymphocytes are a potent source of factors that affect hemopoiesis. The major hemopoietically active factor that is secreted by T lymphocytes is a granulocyte-macrophage colony-stimulating factor (GM-CSF). During an inflammatory response this GM-CSF may act distally on bone marrow cells to increase the number of responding granulocytes and macrophages. A major goal of this project is to purify to homogeneity the T lymphocyte GM-CSF. A highly enriched preparation of GM-CSF has been obtained with the use of high-pressure liquid chromatography. When serum free T lymphocyte-conditioned medium is used as a starting material, the GM-CSF will be purified to homogeneity. Another aim of this project is to determine the nature of the interaction between GM-CSF, IL3 (which is also produced by T lymphocytes), and erythropoietin. It has been shown already tha IL3 potentiates the effects of erythropoietin. However, T lymphocytes secrete about 10-100-fold more GM-CSF than IL3; the molecular basis for the net effect on bone marrow cells when all three factors are present in physiological or pathophysiological (i.e. during inflammation) concentrations is unknown but testable with pure factors. In addition, homogeneous GM-CSF will be subjected to mild proteolysis in an attempt to produce biologically active peptides to determine the minimal structural requirements that are necessary for biological activity. A longterm goal of this project will be to synthesize chemically bioactive peptides and structural analogs that can be used as either stimulatory or inhibitory effectors of hemopoiesis. These studies will further our understanding of the role that T lymphocytes play in regulating hemopoiesis.