: Transforming Growth Factor-B (TGF-beta) is a potent inhibitor of the in vitro proliferation differentiation, and survival of many cell types including B lineage cells. In mice made deficient in TGF-beta 1 by gene targeting (TGF-B 1-/-), there is an expansion of B-cells and their plasma cell progeny ii peripheral lymphoid organs, a phenotype consistent with the anti-proliferative effects of the cytokine By contrast, we did not observe an equivalent expansion of B-cell progenitors in the bone marrow, but instead have identified an age-dependent reduction in the progenitor cells of the TGF-beta 1-/- mice. Results of pilot studies on B lineage progenitor cells from normal mice indicate that very low doses of TGF-beta may promote the survival or differentiation of pre-B-cells. These observations have led to the hypothesis that TGF-beta positively influences B lineage cell progenitors at specific points in their development. To test this hypothesis, to explore mechanisms, and to understand the unexpected features of B-cell development that arise in the absence of TGF-B 1 in vivo, the following Specific Aims are proposed.
Aim 1 : To define the phenotype and differentiation potential of TGF-beta 1-/- B cell progenitors. In this aim the requirement for T-cells in the progenitor cell deficiency will also be examined.
Aim 2 : To define the TGF-beta-responsive stages of normal B-cell development.
Aim 3 : Td examine the need for autocrine TGF-beta in B-cell development and differentiation in vivo using chimeric mouse models.
Aim 4 : To create in vivo models in which B lineage cells are selectively unresponsive to TGF-B. These studies address basic mechanisms of B-cell development and its deregulation by cytokine deficiency. The mouse models created for these experiments may become valuable tools for studies of autoimmune diseases and TGF-beta-resistant human malignancies.
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