Date of Graduation

1991

Document Type

Dissertation/Thesis

Abstract

Stromal cells are key components of the hemopoietic microenvironment of the bone marrow and are now known to function as primary regulators of hemopoietic cell production. This study addresses the role of stromal cells in B lymphocyte production. Initial experiments have established that B lymphocyte development is dependent on the presence of a heterogeneous mixture of stromal cells. In addition, recent studies in this and other laboratories have shown that exposure of stromal cells to cytokines alters their production of hemopoietic growth factors and, as a result, their hemopoietic regulatory function. The experiments presented here specifically demonstrate cytokine-induced changes in the ability of the stromal cell to support pre-B cell formation and consider possible cellular sources of cytokines in the bone marrow. Our results suggest that several of these cytokines influence the pattern of growth factor production by stromal cells and likely alter stromal dependent differentiation and/or proliferation of a number of hemopoietic cells. Our working hypothesis is that through the production of lymphokines, T helper cells along with macrophages residing in the marrow may act to modulate or regulate hemopoiesis. This study also considers the regulation of steady-state B lymphopoiesis. Although IL-7 has been shown to potentiate pre-B cell proliferation, few studies have addressed the possibility that multiple cytokines are involved in progression of proliferation and differentiation in this hemopoietic lineage. Our laboratory has previously described pre-B cell differentiation mediated by the S17 bone marrow stromal cell line. Therefore, we addressed the role of S17, IL-7, and kit-ligand (KL) in progression of pre-B cell development in vitro. The differentiative activity of S17 cells could not be reproduced with IL-7, KL, or co-stimulation with both IL-7 and KL. Proliferation of pre-B cells was clearly shown to be due to IL-7. In addition, IL-7 and S17 cells synergistically costimulated proliferation of lymphoid long-term bone marrow cultured cells. This IL-7 costimulatory activity of S17 could be replaced with KL. These data contribute to a model of regulation of B cell production in the marrow and suggest unique roles for the uncharacterized S17-derived lymphokines in this process.

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