CD4 T CELL DEPENDENT B CELL ACTIVATION IN AIDS LYMPHOMAS

艾滋病淋巴瘤中 CD4 T 细胞依赖性 B 细胞激活

• 批准号: 2108353
• 负责人: DONALD E MOSIER
• 金额: $ 22.94万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 1997-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2108353
• 关键词: AIDS; B lymphocyte; Epstein Barr virus; HIV envelope protein gp120; RNase protection assay; SCID mouse; antibody receptor; cell differentiation; clone cells; enzyme linked immunosorbent assay; genetic strain; helper T lymphocyte; human immunodeficiency virus 1; leukocyte activation /transformation; lymphoma; mixed tissue /cell culture; neoplastic transformation; oncogenes; tumor suppressor genes; virus antigen

One of the frequent consequences of chronic HIV infection is the development of AIDS associated lymphomas. These are uniformly high grade malignancies of B lymphocytes, and they fall into three histological categories: (i) small, noncleaved cell; (ii) large immunoblastic/plasmacytoid cell; and (3), large cell lymphoma. Involvement of Epstein-Barr virus (EBV) is frequently seen in the immunoblastic tumors, while the other tumor categories show frequent c- myc rearrangements and mutations of the p53 tumor suppressor gene. While EBV+ immunoblastic lymphomas have been observed in HIV infection of hu- PBL-SCID mice, the other AIDS-associated lymphomas have not been seen. We propose to study the link between HIV infection and chronic B cell activation, using PBL derived from HIV-infected individuals as well as normal PBL infected in the context of the hu-PBL-SCID model. The specific aims of the project are to determine the response of resting, peripheral blood B cells or tonsillar, germinal center B cells to T cells or T cell clones infected with HIV or expressing HIV gp120 or gp41. CD4 T cell clones will be chosen on the basis of cytokine production to represent either the Th0, Th1, or Th2 subset. Selected combinations of T cell clones and B cells will be introduced into SCID mice to assess the extent of in vivo B cell proliferation, differentiation, and incidence of tumor formation. Peripheral blood B cells, tonsilar B cells, and follicular dendritic cells will be derived from normal donors and PBL from normal and HIV-seropositive donors. EBV seropositive donors who do not give rise to spontaneous tumors will be used. We will also examine expression of B cell genes that might block apoptosis and represent the first step towards malignant transformation under the differing conditions of T cell stimulation outlined in Aim 1. Expression of bcl-2 and the Epstein-Barr virus genes LMP (which transactivates bcl-2 expression), EBNA-2, and ZEBRA will be analyzed by a sensitive RNase protection assay. PBL and germinal center B cells from EBV-positive and EBV-negative donors will be compared. Finally, we will determine the relationship between different HIV-1 strains and specific activation of B cells expressing the VH3 immunoglobulin variable region. Preliminary evidence shows a correlation between the HIV strain used to infect hu- PBL-SCID mice, the rate of CD4 T cell depletion, and the extent of VH3 B cell stimulation. These data suggest that different gp120 molecules may interact differently with the Ig receptor on VH3-expressing B cells, and/or that the extent of CD4 T cell activation following HIV infection differs markedly among different virus strains.

慢性艾滋病毒感染的常见后果之一是 艾滋病相关淋巴瘤的发展。 这些都是统一的高等级 恶性肿瘤的B淋巴细胞，他们分为三个组织学 类别：（i）小，无裂细胞;（ii）大 免疫母细胞/浆细胞样细胞;和（3）大细胞淋巴瘤。 EB病毒（EBV）的参与经常出现在 免疫母细胞肿瘤，而其他肿瘤类别显示频繁的c- myc重排和p53肿瘤抑制基因突变。 而 EBV+免疫母细胞性淋巴瘤已在HIV感染的人中观察到， PBL-SCID小鼠，其他AIDS相关淋巴瘤尚未见到。 我们建议研究HIV感染与慢性B细胞 激活，使用来自HIV感染者的PBL以及 在hu-PBL-SCID模型的背景下感染的正常PBL。 的 该项目的具体目标是确定休息的反应， 外周血B细胞或扁桃体、生发中心B细胞转化为T细胞 或感染HIV或表达HIV gp 120或gp 41的T细胞克隆。 CD4 将根据细胞因子的产生来选择T细胞克隆， 代表Th 0、Th 1或Th 2亚群。 的选定组合 将T细胞克隆和B细胞引入SCID小鼠中以评估免疫应答。 体内B细胞增殖、分化的程度和发生率 肿瘤的形成。 外周血B细胞、扁桃体B细胞和 滤泡树突状细胞将来源于正常供体和PBL 正常和HIV阳性的献血者。EBV血清阳性献血者 将使用不会引起自发性肿瘤的药物。 我们亦会研究 B细胞基因的表达可能会阻止细胞凋亡，并代表 第一步向恶性转化下的不同 目标1中概述的T细胞刺激条件。 bcl-2表达 以及EB病毒基因LMP（其反式激活bcl-2 表达）、EBNA-2和ZEBRA将通过敏感的RNase 保护试验 来自EBV阳性的PBL和生殖中心B细胞， 将比较EBV阴性供体。 最后，我们将确定 不同HIV-1毒株与特异性激活 表达VH 3免疫球蛋白可变区的B细胞。 初步 有证据表明，用于感染人类的艾滋病毒株与 PBL-SCID小鼠、CD 4 T细胞耗竭速率和VH 3表达程度 B细胞刺激。 这些数据表明，不同的gp 120分子 可能与表达VH 3的B细胞上的IG受体不同地相互作用， 和/或HIV感染后CD 4 T细胞活化的程度 不同病毒株间差异显著。