IMMUNE DYSFUNCTION AND AIDS-RELATED TUMORS

免疫功能障碍和艾滋病相关肿瘤

基本信息

批准号：
2084121
负责人：
OTONIEL MARTINEZ-MAZA
金额：
$ 7.03万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-05-01 至 1996-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2084121
关键词：
AIDS B lymphocyte HIV infections Kaposi's sarcoma autocrine growth factor hormone related neoplasm /cancer human immunodeficiency virus human subject immunosuppression interleukin 6 lymphocyte proliferation lymphoma paracrine

项目摘要

Two forms of malignancy are seen in greatly elevated frequency in AIDS and HIV infection: Kaposi's sarcoma (KS) and non-Hodkin's B cell lymphoma (BCL). In this proposal, studies to examine the effects of HIV-induced immune dysfunction on the development and growth of these AIDS-associated tumors are presented. The specific aims are: 1) to define the role of interleukin 6 (IL-6) overproduction in B cell hyperactivation and in the development of BCL associated with HIV infection, 2) to delineate changes in B cell subpopulations, and to define the phenotype of the pre-BCL B cell subset, in HIV infection and AIDS, and, 3) to examine the role of IL-6 and other cytokines in AIDS-related KS. While the dominant immune system dysfunction seen in AIDS is the severe functional and numerical CD4 T cell defect, various other immune system changes, including a marked increase in B cell activity, with elevated levels of serum Ig and spontaneous Ig secretion, and in vivo phenotypic B cell changes characteristic of cellular activation, also are seen in AIDS. The high frequency of B cell malignancies seen in HIV infection may result from this in vivo B cell activation: chronic polyclonal B cell stimulation could increase the size of the target cell pool for chromosomal translocations involving the juxtaposition of an oncogene (c-myc) and an Ig gene, resulting in B cell tumors. Studies described in this proposal will focus on determining the role of HIV-induced IL-6 overproduction in AIDS- associated B cell hyperactivation, and on defining the phenotype of pre- neoplastic B cell subsets in AIDS and HIV infection. These studies will be done using a various cellular and molecular techniques. IL-6 also can act as an autocrine/paracrine growth factor in various human malignancies including multiple myeloma and renal cell carcinoma. In preliminary studies, AIDS-KS cells seen to produce and respond to IL-6. Studies aimed at defining the role of IL-6 and other cytokines in the development and growth of AIDS-associated KS also are described in this proposal. The realization of the specific aims will provide valuable information on the relationship between HIV-induced immune dysfunction and the development of AIDS-associated cancers. This information could form the foundation for future studies on the role of cytokines in AIDS-associated tumor growth and development, or could suggest new forms of treatment for AIDS-related diseases. Also, the realization of these specific aims could lead to new screening techniques able to detect AIDS-related BCL or KS much earlier in the course of tumor development, allowing for earlier clinical intervention.

两种形式的恶性肿瘤在艾滋病和艾滋病中的发生率大大增加 HIV 感染：卡波西肉瘤 (KS) 和非霍德金 B 细胞淋巴瘤（BCL）。在此提案中，研究了艾滋病毒引起的影响免疫功能障碍对这些艾滋病相关患者的发育和生长的影响肿瘤被提出。具体目标是： 1) 明确角色白细胞介素 6 (IL-6) 在 B 细胞过度激活和与 HIV 感染相关的 BCL 的发展，2) 描绘变化 B 细胞亚群，并定义前 BCL B 细胞的表型子集，在 HIV 感染和艾滋病中，3) 检查 IL-6 和艾滋病相关 KS 中的其他细胞因子。虽然艾滋病中主要的免疫系统功能障碍是严重的 CD4 T 细胞功能和数量缺陷、其他各种免疫系统变化，包括 B 细胞活性显着增加，血清 Ig 和自发 Ig 分泌水平以及体内表型 B 细胞激活的细胞变化特征也见于艾滋病。 HIV 感染中 B 细胞恶性肿瘤的高频率可能导致来自体内 B 细胞激活：慢性多克隆 B 细胞刺激可以增加染色体靶细胞库的大小涉及癌基因 (c-myc) 和 Ig 并置的易位基因，导致 B 细胞肿瘤。本提案中描述的研究将重点确定 HIV 诱导的 IL-6 过量产生在 AIDS 中的作用相关的 B 细胞过度激活，以及定义预-的表型艾滋病和 HIV 感染中的肿瘤性 B 细胞亚群。这些研究将使用各种细胞和分子技术完成。 IL-6 还可以在多种人类细胞中充当自分泌/旁分泌生长因子恶性肿瘤包括多发性骨髓瘤和肾细胞癌。在初步研究发现，AIDS-KS 细胞能够产生 IL-6 并对其做出反应。研究旨在明确 IL-6 和其他细胞因子在与 AIDS 相关的 KS 的发展和生长也在本文中进行了描述提议。具体目标的实现将为以下方面提供有价值的信息： HIV引起的免疫功能障碍与发育的关系与艾滋病相关的癌症。这些信息可以构成基础细胞因子在艾滋病相关肿瘤生长中的作用的未来研究的发展，或可能提出治疗艾滋病相关的新形式疾病。此外，这些具体目标的实现可能会带来新的能够更早地检测出艾滋病相关 BCL 或 KS 的筛查技术肿瘤发展过程，以便更早进行临床干涉。