MOLECULAR PATHWAYS OF LEUKOCYTE HOMING TO BONE MARROW

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The ability of hematopoietic stem cells (HSC) to home from the blood into specialized microenvironments in the bone marrow underlies the clinical success of bone marrow transplantation, which is becoming increasingly important for the treatment of a variety of diseases. In spite of the clinical importance of bone marrow transplantation, the molecular mechanisms which are responsible for HSC traffic to the bone marrow are poorly understood. Understanding these mechanisms would make possible manipulation of HSC homing receptor expression and/or activity, and may improve the efficacy of bone marrow transplantation in a variety of clinical settings. We hypothesize that HSC use at least some of the same pathways and adhesion molecules as normal, mature leukocytes use during their interaction with endothelium and subsequent passage into tissues. This proposal details experiments to determine the role of selectins in HSC traffic, especially homing to bone marrow. Selectins are a family of three carbohydrate-binding adhesion molecules well documented to play a critical role in the regulation of normal leukocyte traffic, specifically in the initial interactions of leukocytes with endothelium. In the first specific aim, we will evaluate the role of the selectins in HSC traffic by testing whether transplantation of bone marrow cells from appropriate selectin knockout mice can reconstitute lethally irradiated wild type littermates; and conversely, whether transplantation of normal bone marrow cells can reconstitute lethally irradiated selectin knockout mice. Reconstitution will be assess by long term (greater than 100 days) survival of the irradiated mice, and will be confirmed by analysis of multilineage reconstitution from marked donor bone marrow cells. In specific aim #2, we will determine whether normal plasma cells, which like HSC also exhibit a strong tendency to home into bone marrow, also use selectins in the course of their migration into bone marrow, and which other adhesion pathways are used by these cells. These experiments will identify the role selectins play in HSC and plasma cell traffic to bone marrow, and will begin to define at the molecular level the pathways of leukocyte homing to bone marrow.