PATHOGENESIS OF EBV ASSOCIATED AIDS LYMPHOMAS

获得性免疫缺陷综合征（艾滋病）患者 发生B细胞淋巴瘤的风险增加， EB病毒（EBV）感染呈阳性。 EB病毒的直接作用 在这些淋巴瘤的病因是怀疑，但病毒宿主 导致淋巴瘤发生的相互作用仍不清楚。 的 我们研究的长期目标是确定EBV如何调节 在B细胞中生长、分化和死亡的细胞过程， 在严重的宿主免疫缺陷的背景下， 国家实现了。 我们建议在细胞中检查这些过程 I）EBV感染的淋巴母细胞样细胞系 (LCL)ii）用EBV基因转染的B细胞系; iii）B细胞 来源于用EBV感染的重组的SCID小鼠的淋巴瘤 B细胞（hu-PBL-SCID小鼠）; iv）AIDS相关淋巴瘤（ARL）。 到 破译了马槟榔碱介导的自分泌生长在 淋巴瘤发生、hu-PBL-SCID淋巴瘤、ARL和LCL将在 分析生长调节细胞因子和细胞因子的表达 受体。 然后，我们将使用中和性抗细胞因子单克隆抗体， 确定这三种细胞类型的体外生长或 SCID小鼠淋巴瘤的发生依赖于细胞因子 表情 此外，我们将使用EB病毒基因转染的细胞系， 研究EBV蛋白在细胞因子调节中的作用， 细胞因子受体表达。 评估EBV感染是否改变了 B细胞、hu-PBL-SCID淋巴瘤、ARL、 和LCL将在体外分析其对各种 细胞死亡的诱导物。 此外，我们将评估三个细胞 前死亡基因和抗死亡基因的相对表达水平的类型， 我们将使用EB病毒基因转染子来发现病毒宿主 相互作用导致改变细胞死亡程序。 评价 分化过程在淋巴瘤发生中的作用，ARL将是 评估免疫表型异质性和病毒模式 基因表达。 为了模拟ARL中的差异变化，我们将 从hu-PBL分离淋巴母细胞样和浆细胞样细胞亚群， SCID淋巴瘤和检测亚型特异性差异的模式 细胞生长、细胞死亡以及相关宿主和病毒基因的表达。 最后，将在体外筛选细胞因子以确定其诱导细胞凋亡的能力。 分化的淋巴母细胞亚群和LCL，并改变他们的 EB病毒基因表达模式。 这些研究的结果应该 有助于设计阻断生长或诱导死亡的疗法 或终末分化。

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.