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(AFB1)等致癌物的诱导能力 在动物身上的免疫抑制已经被很好地记录下来了。然而，分析 其中涉及的分子和细胞机制尚未得到解决。 沙斯塔品系的彩虹鲑鱼，除了是一种极好的动物外 黄曲霉毒素B_1诱导肝细胞癌的模型 证明了对该制剂的免疫功能障碍的诱导。这些 功能障碍与无法形成免疫记忆有关。 可能是免疫调节缺陷的结果，或者是 非淋巴样细胞或淋巴样细胞。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，这项研究的目标是 1)对免疫反应进行分子和细胞分析 在暴露于AFB1的鱼中产生以确定这种免疫的来源 功能障碍和2)检查其他遗传毒性致癌物/免疫毒物 用于类似形式的免疫抑制。 暴露于黄曲霉毒素B_1的动物产生的抗体的精细特异性的变化 这一定是由于B细胞群体的抗体表达发生了变化。 这可能是通过改变记忆调节来实现的 发展或通过直接作用于B淋巴细胞。特征描述 通过精细的特异性、谱型和独特型分析，抗体将 允许对这些抗体群体进行“指纹识别”，进而 将被用来确定抗体谱系的明显转变是否 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。 这种记忆障碍的细胞起源将通过使用 前体频率分析，有丝分裂分析与细胞 分割技术和采用的细胞转移。致力于以下方面的研究 胚胎发育和体外培养过程中细胞机制的研究 AFB1的暴露将需要发展自体和同基因细胞 转移系统。使用同基因品系的鲑鱼也将是 对免疫学研究大体上有利，并通过以下方式提供手段 从而实现肿瘤细胞系的长期繁殖和研究。