Newly formed Beta lymphocytes are generated from progenitor cells which reside in the bone marrow of postnatal mice and man. Although substantial progress has been made in defining cell lineage relationships for Beta cell precursors, less is known about regulatory events which potentiate or retard these differentiation events. In addition, several observations suggest that regulation of Beta lymphopoiesis may be intimately tied to regulatory events for other developing lineages in that tissue. This project explores the developmental immunobiology of cells and molecules which regulate the tempo of pre-Beta cell and subsequently Beta cell formation. Our studies focus on bone marrow stromal cell lines derived from long term bone marrow cultures which differ in their ability to potentiate pre-Beta cell generation, single cloned stromal cell lines also have the capacity to potentiate myeloid cell formation. These regulatory roles are mutually exclusive in culture and reasons for this functional switching phenomenon are under study. Importantly, we have determined that the hemopoietic regulatory capacity of these stromal cell lines can be altered by exposure to rIL-1alpha and rIL-4 or conditioned media containing native IL-1 or IL-4. This effect was not due to contaminating endotoxin nor to binding to the extracellular matrix. In the project presented here, we propose to determine changes in stromal cell gene expression which result from treatment with IL-1 or IL-4. We will focus particular attention of the role of IL-4, IL-6, and CSF in regulating pre-Beta cell formation. We will also address the possibility that T-helper cells are involved in this process. Several studies have indicated that hemopoietic growth factors bind to proteoglycans in the extracellular matrix and we will determine whether this mechanism operates in Beta lymphopoietic systems. Finally, our studies will address reasons for the observed diminution of pre-Beta cell formation with advancing age in mice. Our long range goals are to better understand regulatory mechanisms which act on the developing Beta lineage and relate these findings to regulatory dyscrasias of immunodeficiency disease and leukemias of man. These findings may also be important in considerations of using interleukin and CSF therapy in humans.
Showing the most recent 10 out of 13 publications
