The principal aims of this research are to purify and determine the structural and functional properties of T cell-derived glucosteroid response modifying factor (GRMFT). GRMFT is a newly discovered leukocyte hormone that protects T helper cells and the progenitors of granulocytes and macrophages from suppression by glucosteroids. Preliminary studies strongly indicate that GRMFT is distinct from other well characterized leukocyte hormones. Although further research is required to establish the physiological and clinical significance of GRMFT, its selective activity on T helper cells suggest that in combination with elevated glucosteroids, GRMFT increases the ratio of T helper to T suppressor cells. Thus its physiological role appears to insure appropriate balance of regulatory T cells during stress. Failure of this pathway may result in immune deficiency while prolonged or excess production may contribute to autoimmunity. Furthermore, excess GRMFT production may explain the apparent steroid resistance of neoplastic cells from some patients with leukemia. We propose first to purify GRMFT from a murine T cell hybridoma by a combination of salt fractionation, chromatographic, and electrofocusing procedures. We will also determine if normal human T cells and T cell lines produce GRMFT and will purify GRMFT from these sources. We will produce conventional and monoclonal antibodies to GRMFT to develop radio and enzyme lilnked immune assays and to facilitate studies of target cells and GRMFT receptors. In addition to purifying putative target cells from normal tissues we will seek to identify or produce cell lines that are targets of GRMFT. Such cell lines (or adequately purified target cells from normal tissues) will be used to study the mechanisms by which GRMFT blocks cellular responses to glucosteroids.
