MOLECULAR IMMUNOBIOLOGY OF AIDS-LYMPHOMA

艾滋病淋巴瘤的分子免疫生物学

• 批准号: 2008993
• 负责人: Paolo Casali
• 金额: $ 25.56万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-01-19 至 1998-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2008993
• 关键词: AIDS; AIDS related neoplasm /cancer; B lymphocyte; Burkitt's lymphoma; antibody formation; antibody specificity; cellular pathology; human tissue; leukocyte activation /transformation; molecular cloning; molecular pathology; monoclonal antibody; neoplastic transformation; nonHodgkin's lymphoma; point mutation; protooncogene; tissue /cell culture; tumor suppressor genes

The long-term goal of this proposal is to gain insight into the cellular and molecular mechanisms underlying B cell clonal expansion and malignant transformation in AIDS-associated non Hodgkin's lymphoma (NHL). As a result of the introduction of relatively effective anti-retroviral therapy and the consequent higher survival rate, NHLs have become important causes of pathology in AIDS patients. In these patients, most NHLs are Burkitt- type B cell lymphomas, and display features similar to those of sporadic Burkitt's lymphoma (BL) occurring in HIV-negative patients, including t(8;14), t(8;22) or t(2;8) chromosomal translocation and c-myc proto- oncogene activation. This represents an important, but not, perhaps, sufficient event in lymphomagenesis. Full malignant transformation would require either activation of a second proto-oncogene or a stochastic second event, such as infection with Epstein-Barr virus (EBV), a powerful B lymphotropic transforming agent. EBV is present in virtually all endemic (African) BLs, but it is found only in a minority of AIDS BLs, suggesting that other B cell "driving" cofactors underlie the malignant transformation of these lymphocytes. This view is further supported by the generalized B cell "hyperactivity", often associated with lymph node follicular hyperplasia, found in a significant proportion of AIDS patients prior to tumoral outgrowth; and by our preliminary findings showing that the variable segments of the specific anti-rd blood cell i/I antigen autoantibodies produced by two different AIDS-associated BLs bear imprints (somatic point-mutations) that are characteristic of a persistent antigenic stimulation. We hypothesize that a mechanism of self or foreign antigen-driven B cell clonal expansion and selection precedes and/or is associated with the cellular events leading to malignant transformation in AIDS BL. Conversely, antigenic stimulation may play a less important or negligible role in the emergence and/or sustenance of neoplastic B cells in the endemic variety of BL. To test our hypothesis, we propose to analyze the antigen specificity of the antibodies produced by AIDS BLs, and determine whether their variable segments contain somatic point- mutations in a fashion consistent with a process of antigen-driven clonal selection of such mutations. In addition, we propose to verify whether progenitors of the neoplastic clonotype are present among "non-neoplastic" B cells, as defined by phenotypic and genotypic analysis, obtained prior to tumoral outgrowth. The molecular features of AIDS BL will be compared with those derived from the analysis of the sporadic and endemic forms of the tumor. The demonstration that a process of Ag-driven clonal expansion and selection is an important event or cofactor, along with the characteristic genetic lesions, in AIDS-associated lymphomagenesis would provide one of the first indications that the inherent function of the (immune) cells involved in the neoplastic process are crucial for tumor development, and may provide the basis for specific immune intervention.

该提案的长期目标是洞悉蜂窝 B细胞克隆膨胀和恶性肿瘤的基础机制和分子机制 与艾滋病相关的非霍奇金淋巴瘤（NHL）的转化。 作为 引入相对有效的抗逆转录病毒疗法的结果 随之而来的较高存活率，NHL已成为重要原因 艾滋病患者的病理学。 在这些患者中，大多数NHL是Burkitt- B型细胞淋巴瘤和显示特征类似于零星的特征 伯基特的淋巴瘤（BL）发生在HIV阴性患者中，包括 t（8; 14），t（8; 22）或t（2; 8）染色体易位和c-myc proto- 癌基因激活。 这代表了一个重要但不是 淋巴作用的足够事件。 完全的恶性转变将 需要激活第二个原型癌基因或随机性 第二个事件，例如爱泼斯坦 - 巴尔病毒（EBV）的感染，有力 B淋巴细胞转化剂。 EBV几乎存在于所有 地方性（非洲）BLS，但仅在少数艾滋病中发现 提示其他B细胞“驱动”辅助因子是恶性的 这些淋巴细胞的转化。 这种观点得到了进一步的支持 广义B细胞“多动症”，通常与淋巴结有关 卵泡增生，在很大一部分艾滋病患者中发现 在肿瘤生长之前；并通过我们的初步发现表明 特定抗RD血细胞I/I抗原的可变段 由两个不同的艾滋病相关的BLS烙印产生的自身抗体 （躯体突变）是持续的特征 抗原刺激。 我们假设自我或外国的机制 抗原驱动的B细胞克隆膨胀和选择先于和/或IS 与导致恶性转化的细胞事件相关 艾滋病BL。 相反，抗原刺激的重要性可能不太重要或 在肿瘤B细胞的出现和/或维持中的作用可忽略不计 在流行的BL中。 为了检验我们的假设，我们建议 分析AIDS BLS产生的抗体的抗原特异性， 并确定它们的可变段是否包含躯体点 - 以抗原驱动克隆的过程一致的方式突变 选择此类突变。 此外，我们建议验证是否 肿瘤clonotype的祖细胞存在于“非塑性”中 由表型和基因型分析定义的B细胞获得了先验 肿瘤生长。 将比较艾滋病的分子特征 从零星和流行形式的分析得出的 肿瘤。 AG驱动克隆扩张过程的演示 选择是一个重要的事件或辅助因子， 特征性的遗传病变，在与艾滋病相关的淋巴作用中 提供了第一个迹象之一 （免疫）涉及肿瘤过程的细胞对于肿瘤至关重要 开发，并可能为特定的免疫干预提供基础。