PATHOGENESIS OF EBV ASSOCIATED AIDS LYMPHOMAS

获得性免疫缺陷综合征(艾滋病)患者包括 患B细胞淋巴瘤的风险增加 EB病毒(EBV)感染阳性。EBV的直接作用 这些淋巴瘤的病因是可疑的，但病毒宿主 导致淋巴肥大的相互作用尚不清楚。这个 我们研究的长期目标是确定EBV如何调节 B细胞的生长、分化和死亡的细胞过程 在严重的宿主免疫缺陷的情况下，恶性 状态达到了。我们建议在细胞中研究这些过程 来源于四个来源：i)EBV感染的淋巴母细胞系 (LCL)；II)转EBV基因的B细胞；III)B细胞 经EB病毒感染重组的SCID小鼠来源的淋巴瘤 B细胞(Hu-PBL-SCID小鼠)；iv)艾滋病相关淋巴瘤(ARL)。至 破译细胞因子介导的自分泌生长在糖尿病中的作用 淋巴肿大、HU-PBL-SCID淋巴瘤、ARL和LCL将是 生长调节性细胞因子及细胞因子的表达分析 感受器。然后我们将使用中和抗细胞因子单抗来 确定这三种细胞类型在体外的生长还是 SCID小鼠淋巴瘤的发生依赖于细胞因子 表情。此外，我们还将使用EBV基因转基因的细胞株来 检测EBV蛋白在细胞因子和细胞因子调节中的作用 细胞因子受体表达。评估EBV感染是否会改变 B细胞、HU-PBL-SCID淋巴瘤、ARL、 和LCL将在体外分析它们对不同种类的 细胞死亡的诱导者。此外，我们将评估这三个单元格 致死基因和抗死亡基因的相对表达水平的类型， 我们将使用EBV基因转染体来发现病毒宿主 导致细胞死亡程序改变的相互作用。要评估 分化过程在淋巴增生症中的作用 评估免疫表型的异质性和病毒的模式 基因表达。为了模拟ARL的差异化变化，我们将 人外周血淋巴细胞亚群和浆细胞亚群的分离 SCID淋巴瘤及其亚型特异性差异的检测 细胞生长、细胞死亡以及相关宿主和病毒基因的表达。 最后，细胞因子将在体外筛选它们的诱导能力。 淋巴母细胞亚群和LCL的分化及其改变 EBV基因表达的模式。这些研究的结果应该是 有助于设计阻止生长或导致死亡的治疗方法 或ARL的终末期分化。

Individuals with Acquired Immune Deficiency Syndrome (AIDS) are at increased risk for the development of B cell lymphomas that are positive for Epstein-Barr virus (EBV) infection. A direct role for EBV in the etiology of these lymphomas is suspected, but the virus-host interactions that contribute to lymphomagenesis remain unclear. The long-term goals of our studies are to determine how EBV regulates the cellular processes of growth, differentiation, and death in B cells such that, in the context of profound host immunodeficiency, a malignant state is achieved. We propose to examine these processes in cells derived from four sources: I) EBV-infected lymphoblastoid cell lines (LCL); ii) B cell lines transfected with EBV genes; iii) B cell lymphomas derived from SCID mice reconstituted with EBV-infected B cells (hu-PBL-SCID mice); iv) AIDS-related lymphomas (ARL). To decipher the role of cytokine-mediated autocrine growth in lymphomagenesis, hu-PBL-SCID lymphomas, ARL, and LCL will be analyzed for the expression of growth-regulating cytokines and cytokine receptors. We will then use neutralizing anti-cytokine mAbs to determine whether the growth of these three cell types in vitro or the development of lymphomas in SCID mice is dependent upon cytokine expression. Also, we will use EBV gene-transfected cell lines to examine the role of EBV proteins in the regulation of cytokine and cytokine receptor expression. To assess whether EBV infection alters distinct apoptotic pathways in B cells, hu-PBL-SCID lymphomas, ARL, and LCL will be analyzed in vitro for their sensitivity to various inducers of cell death. In addition, we will evaluate the three cell types for the relative levels of expression of pro-and anti-death genes, and we will use EBV gene-transfectants to uncover virus-host interactions leading to altered cell death programs. To evaluate the role of differentiative processes in lymphomagenesis, ARL will be assessed for immunophenotypic heterogeneity and for patterns of viral gene expression. To model differentiative change in the ARL, we will isolate lymphoblastoid and plasmacytoid cell subsets from hu-PBL- SCID lymphomas and test for subset-specific differences in patterns of cell growth, cell death, and expression of relevant host and viral genes. Lastly, cytokines will be screened in vitro for their capacity to induce differentiation of the lymphoblastoid subset and LCL, and to alter their patterns of EBV gene expression. Results from these studies should contribute to the design of therapies to block growth or to induce death or terminal differentiation of ARL in patients.