SELECTIVE REDUCTION OF IMMUNE CLEARANCE BY ETHANOL

乙醇选择性降低免疫清除率

• 批准号: 3112954
• 负责人: RONALD P MESSNER
• 金额: $ 15.79万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-02-01 至 1994-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3112954
• 关键词: Kupffer's cell; affinity chromatography; alcoholic beverage consumption; alcoholism /alcohol abuse; complement deficiency; complement receptor; cortisol; drug metabolism; gel electrophoresis; immunity; immunodiffusion; immunoglobulin G; infection; laboratory mouse; liver metabolism; liver pharmacology; macrophage; mathematical model; phagocytosis; radioimmunoassay; radionuclides; toxicology

This proposal examines the effect of ethanol on immune clearance, an important immune mechanism of host defense. Preliminary experiments demonstrated that chronic ethanol feeding of BALB/c mice decreases in vivo immune clearance mediated by complement(C3b), but does not effect clearance mediated by the Fc portion of IgG. This newly recognized defect may be important in the susceptibility to infection associated with the use of ethanol. The parameters of this clearance defect will be defined and the hypothesis that it's selective nature is the result of the preferential effect of ethanol on fixed tissue macrophages in the liver will be tested. Data from clearance of IgG-sensitized erythrocytes are analyzed by an iterative curve fitting process based on a rate equation which was derived from a validated model of immune clearance. Four rate constants are obtained that define the major steps in immune clearance: hepatic(C3b) sequestration, hepatic(C3b) mediated phagocytosis, C3b deactivation and return of deactivated cells back to the circulation and splenic (Fc) mediated clearance. The technique allows independent quantitative evaluation of the C3b and Fc mediated in vivo clearance pathways under a variety of experimental conditions. The dose range of ethanol effecting clearance as well as the timing and duration of the defect, the difference in acute bolus and chronic feeding and the effect in another mouse strain known to ingest ethanol will be determined. The selective effect on complement mediated clearance will be confirmed by increasing the role of Fc mediated clearance to bring out subtle changes in the Fc pathway by treatment with cobra venom factor and the use of a mouse strain with a genetic relative defect in complement clearance. The relative number of functional C3b receptors and the rates constant governing their activity will be determined in ethanol and control mice by kinetic techniques. The hypothesis that the selective decrease in complement clearance is due to preferential damage to Kupffer cells by products of ethanol metabolism in hepatocytes will be examined using a combination of surgical and kinetic techniques as well as selective inhibition of the steps in ethanol metabolism with 4-methyl pyrazole and cyanamide. Knowledge gained in these studies should establish one mechanism through which alcohol can act as a cofactor in the development of infectious diseases.

这项提案研究了乙醇对免疫清除的影响， 宿主防御重要免疫机制。初步实验 结果表明，BALB/c小鼠的慢性乙醇喂养降低了体内 补体（C3 b）介导的免疫清除，但不影响清除 由IgG的Fc部分介导。这种新发现的缺陷可能是 重要的是与使用相关的感染易感性 乙醇将定义此间隙缺陷的参数， 假设它的选择性本质是偏好的结果， 将测试乙醇对肝脏中固定组织巨噬细胞的影响。 IgG致敏红细胞的清除数据通过以下方法分析： 迭代曲线拟合过程的基础上的速率方程，推导出 免疫清除的有效模型。四个速率常数为 获得定义免疫清除主要步骤的数据：肝脏（C3 b） 隔离，肝（C3 b）介导的吞噬作用，C3 b失活和 失活细胞返回循环和脾脏（Fc） 介导清除率。该技术允许独立定量 评价C3 b和Fc介导的体内清除途径， 各种实验条件。乙醇的剂量范围 清除以及缺陷的时间和持续时间，差异 在急性推注和慢性喂养中以及在另一种小鼠品系中的作用 已知摄入乙醇的人将被确定。选择性影响 补体介导的清除将通过增加 Fc介导的清除，通过以下方式在Fc途径中引起细微变化： 用眼镜蛇毒因子治疗和使用具有 补体清除的遗传相对缺陷。的相对数量 功能性C3 b受体和控制其活性的速率常数 将通过动力学技术在乙醇和对照小鼠中测定。的 假设补体清除率的选择性降低是由于 乙醇代谢产物对枯否细胞的优先损伤 将使用手术和动力学联合检查肝细胞 技术以及在乙醇中的步骤的选择性抑制 代谢与4-甲基吡唑和氰胺。 在这些研究中获得的知识应通过以下方式建立一个机制： 酒精可以作为一种辅助因子在传染性疾病的发展， 疾病