In contrast to the extensive information available about the phenotypic and functional characteristics of mature natural killer (NK) cells and the factors regulating their activity, there is a paucity of information about earlier stages of NK development. Evidence indicates that 5-- fluorouracil (5FU)-resistant NK progenitor cells are present in the bone marrow, (BM), and in short term culture studies, we previously demonstrated that interleukin I (IL1) and IL2 play sequential roles in the promotion of differentiation into mature NK cells. An in vitro system for long-term culture of rat or mouse bone marrow cell (LTBMC), that enriches for NK precursor cells recently has been developed in our laboratories. Based on our studies to date and those published by other investigators, we have formulated a hypothetical model of NK cell differentiation from stem cells of mouse BM. The main goal of the proposed studies is to test various aspects of this model, to provide a conceptual framework and needed information and approaches for improvements in NK cell-based therapy. Specifically we propose to continue to define the stages of differentiation of NK cells from their stem cells and progenitors by: a) generating enriched populations of NK precursors and IL2-responsive cells in NK LTBMC; b) using the enriched populations of NK cells precursor cells in LTBMC and earlier progenitor cells to produce new monoclonal antibodies (mAbs) against NK progenitor and precursor cells; c) characterizing the phenotype and of each of these cells in LTBMC; c) determining whether or not purified lymphohematopoietic stem cells can be induced to differentiate into NK cells in LTBMC and e) evaluating the in vivo transplantability of NK progenitor and precursor cells. We will also examine the relationship of the NK lineage to other lineages of BM-derived cells, by determining the ability of purified NK progenitor or precursor cells to develop into cells of other lineages. In addition, the regulatory effects of BM stromal cells, T cells, and of cytokines in the differentiation of NK cells will be evaluated. These studies will include the evaluation of the role of IL2 and other cytokines in the in vivo development of NK cells.

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