Follicular lymphomas are incurable diseases. Morphologically, they recapitulate the architecture of normal germinal centers of secondary lymphoid follicles. A unique component common to follicular lymphomas and normal germinal centers is the follicular dendritic cell (FDC). FDCs are athe major supporting cell in the germinal center microenvironment in which B cells normally differentiate. FDCs are hypothesized to be essential to the regulation of normal B cell growth and differentiation into memory or antibody secreting cells. The interaction of B cells with FDCs is mediated principally by the adhesion receptor VLA -4 is involved in signaling to B cells through activation of the tyrosine kinase pathway. Recent evidence suggests that integrin mediated signaling is critical to the growth and survival of normal and malignant cells, and may be important to the control of programmed cell death. A central hypothesis to be investigated in this proposal is that beta1 integrin mediated signaling is fundamentally important to the regulation of B cell growth and survival. In collicular lymphomas, the adhesive interaction of FDCs with neoplastic B cells is intact and employs the same receptor-ligand pair. Presently, there is limited understanding of the nature of the influences of FDCs upon normal B cells and whether FDCs they can affect malignant B cell growth . The primary goal of this project is to investigate the interactions of normal and neoplastic B cells with FDCs. To this end we plan to undertake four Specific Aims. First to investigate beta1 integrin mediated signaling in normal and malignant B cells through studies of tyrosine phosphorylated proteins. Second to optimize the in vitro conditions for expansion and maintenance and maintenance of FDCs. Third to examine the effects of FDCs on the growth and survival of normal B cells and to identify the signals which mediate those effects. Fourth to examine the effects of FDCs on the growth and survival of follicular lymphoma cells. An understanding of the cell-cell interactions and signaling which may occur between FDCs and follicular lymphoma cells may provide future therapeutic strategies with which to modulate the growth of these tumors.
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