MECHANISMS OF CARCINOGEN-INDUCED IMMUNE DYSFUNCTION

致癌物引起的免疫功能障碍的机制

• 批准号: 3254114
• 负责人: STEPHEN L KAATTARI
• 金额: $ 11.14万
• 依托单位: OREGON STATE UNIVERSITY
• 依托单位国家: 美国
• 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/3254114
• 关键词: B lymphocyte; aflatoxins; anamnestic reaction; antibody formation; antibody specificity; antiidiotype antibody; antiserum; autologous transplantation; benzanthracenes; benzopyrenes; cellular pathology; chemical carcinogen; cyclophosphamide; disease /disorder model; electrofocusing; enzyme linked immunosorbent assay; immune tolerance /unresponsiveness; immunity; immunoglobulin genes; immunoglobulin idiotypes; immunologic memory; immunotoxicity; laboratory mouse; mitogens; molecular pathology; monoclonal antibody; nitrophenol; passive immunization; radiation dosage; tissue /cell culture; trout /salmon

The ability of aflatoxin B1 (AFB1) and other carcinogens to induce immunosuppression in animals has been well documented. However, analysis of the molecular and cellular mechanisms involved have yet to be addressed. The Shasta strain of rainbow trout, aside from being an excellent animal model for the induction of hepatocellular carinomas by AFB1, also demonstrates the induction of immune dysfunctions to this agent. These dysfunctions are related to an inability to develop immunological memory and may be the result of deficits in immune regulation either by non-lymphoid or lymphoid cells. Conversely, they may be due to direct genotoxic damage to the B lymphocyte. Thus, the goals of this study are to 1) perform molecular and cellular analyses of the immune responses generated in AFB1-exposed fish to determine the origin of this immune dysfunction and 2) to examine other genotoxic carcinogens/immunotoxicants for similar forms of immunosuppression. Shifts in fine specificity of antibodies generated in AFB1 -exposed animals must be due to the altered expression of antibody by B cell populations. This may occur either through changes in the regulation of memory development or by direct effects on B lymphocytes. Characterization of antibodies by fine specificity, spectrotypic, and idiotypic analyses will permit the "fingerprinting" of these antibody populations, which in turn will be used to determine if the apparent shift in antibody repertoires are due to random or non-random processes. These techniques will also provide the necessary tools that will be required for future genetic analyses. The cellular origin of this memory dysfunction will be addressed by the use of precursor frequency analysis, mitogenic assays coupled with cellular partitioning techniques and adoptive cell transfers. Studies devoted to the study of the cellular mechanisms involved during embryonic and in vitro AFB1 exposure will require the development of autologous and syngeneic cell transfer systems. The use of syngeneic strains of trout will also be of benefit to immunological research in general and also provide the means by which the long-term propagation and study of tumor lines may be realized.

黄曲霉毒素B1（AFB 1）和其他致癌物质诱导 动物中的免疫抑制已经有充分的文献记载。 然而，分析 所涉及的分子和细胞机制尚未得到解决。 沙斯塔虹鳟鱼除了是一种很好的动物 AFB 1诱导肝细胞癌的模型， 证明了对该试剂的免疫功能障碍的诱导。这些 功能障碍与免疫记忆的发展能力有关 可能是免疫调节缺陷的结果， 非淋巴细胞或淋巴细胞。 相反，它们可能是由于直接 对B淋巴细胞的遗传毒性损伤。 因此，本研究的目标是 1)对免疫反应进行分子和细胞分析 在AFB 1暴露的鱼产生，以确定这种免疫的起源 功能障碍和2）检查其他遗传毒性致癌物/免疫毒物 用于类似的免疫抑制 AFB 1暴露动物产生的抗体精细特异性的变化 这一定是由于B细胞群的抗体表达改变所致。 这可能是通过改变记忆的调节 发展或直接作用于B淋巴细胞。 表征 通过精细的特异性、谱型和独特型分析， 允许这些抗体群体的“指纹”， 将用于确定抗体库的明显变化是否 由于随机或非随机过程。 这些技术还将提供 未来基因分析所需的必要工具。 这种记忆功能障碍的细胞起源将通过使用 前体频率分析，促有丝分裂试验， 分配技术和过继细胞转移。 研究致力于 研究胚胎和体外过程中涉及的细胞机制 AFB 1暴露将需要自体和同基因细胞的发育 传输系统。 使用同源品系的鳟鱼也将是 有利于免疫学研究的一般，也提供了手段， 可实现肿瘤细胞系的长期增殖和研究。