Newly formed B lymphocytes are generated from progenitor cells which reside in the fetal liver and postnatal bone marrow of mice and man. Lymphopoietic events which precede the emergence of B cells and their subsequent participation in immune responses are poorly understood. This project explores the developmental immunobiology of B lymphocyte progenitor cells and proposes to define regulatory events which control their survival, proliferation, and differentiation in hemopoietic tissues. It is proposed that failures of either this cascade of regulatory events or in the orderly progression of B lineage cells through these developmental cell compartments may result in immunodeficiency diseases of the humoral immune system (agammaglobulinemia or dysgammaglobulinemia) and that these regulatory events may play a role in the progression of B lineage leukemias. In preliminary studies presented here, we have defined two sources of regulatory factors which potentiate the generation of murine pre-B cells from their progenitors in vitro. One of these is a bone marrow stomal cell line; the other, urinary preparations from a patient with cyclic neutropenia. It will now be imperative to biochemically purify and utilise these regulatory factors to probe the cellular identity of B lineage progenitors, cellular sources of B lymphopoietic factors, and the in vivo relevance of these observations. The synergy of multiple hemopoietic factors has been demonstrated in myeloid development and we will investigate the possibility that similar regulatory events can be demonstrated for developing B lineage cells. An important part of this project is the development of improved assays for B lineage progenitor cells and regulatory events which affect them. These assays will be utilised to better define early cells in the lineage which may function as stem cells for B lymphocyte development. In addition, the relationship of developmental regulatory influences for other blood cell lineages will be related to progression of B lymphocyte development and evaluated in terms of coordinated events which accompany hemopoietic manipulation. These studies will also address the role of regulatory factors and cells in the proliferation of transformed B lineage leukemias of mice. Our long range goals are to better understand regulatory mechanisms which potentiate the proliferation and differentiation of B lymphocyte precursors and to relate these regulatory events to immunodeficiency diseases and leukemias of man.
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