GERMINAL CENTER INTERACTIONS OF NORMAL/MALIGNANT B CELLS

滤泡性淋巴瘤是不治之症。 从形态学上讲， 概括了正常的生殖中心的结构， 淋巴滤泡 滤泡性淋巴瘤的一个共同的独特组成部分， 正常的生发中心是滤泡树突细胞（FDC）。 FDCs是 在生发中心微环境中， B细胞正常分化。 FDCs被假设为是必不可少的， 调节正常B细胞生长和分化为记忆或 抗体分泌细胞。 B细胞与FDC的相互作用是通过 主要通过粘附受体VLA-4参与向B的信号传导 细胞通过激活酪氨酸激酶途径。 最近的证据 表明整合素介导的信号传导对生长至关重要， 正常和恶性细胞的存活，并且可能对控制 程序性细胞死亡 在这个研究中要研究的一个中心假设是 建议是β 1整合素介导的信号传导从根本上 对调节B细胞生长和存活很重要。 在丘 在淋巴瘤中，FDCs与肿瘤性B细胞的粘附相互作用 完整的并且使用相同的受体-配体对。 目前， 有限的理解的性质的影响，FDCs对正常的 B细胞和FDCs是否可以影响恶性B细胞的生长。 的 该项目的主要目标是研究正常的 和肿瘤性B细胞与FDC。 为此，我们计划开展四项 具体目标。 首次研究β 1整合素介导的信号传导 正常和恶性B细胞通过研究酪氨酸磷酸化 proteins. 二是优化体外扩增条件， 维护和保养FDC。 第三，研究固定债务工具的影响 对正常B细胞生长和存活的影响，并识别 这些影响的媒介。 第四，研究功能界别对 滤泡性淋巴瘤细胞的生长和存活。 的理解 细胞间相互作用和信号传导可能发生在FDC和 滤泡性淋巴瘤细胞可能提供未来的治疗策略， 来调节这些肿瘤的生长

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.