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.

该提案研究了乙醇对免疫清除的影响，这是 宿主防御的重要免疫机制。初步实验 证明BALB/c小鼠的慢性乙醇进食会减少体内 补体介导（C3B）介导的免疫清除率，但不影响清除率 由IgG的FC部分介导。这个新认识的缺陷可能是 对于与使用相关的感染的敏感性很重要 乙醇。将定义此清除缺陷的参数，并 假设它是选择性性质是优先的结果 将测试乙醇对肝脏中固定组织巨噬细胞的影响。 来自IgG敏化的红细胞清除的数据由A分析 基于得出的速率方程的迭代曲线拟合过程 从经过验证的免疫清除模型中。四个费率常数是 获得了定义免疫清除的主要步骤：肝（C3B） 隔离，肝（C3B）介导的吞噬作用，C3B失活和 将停用的细胞返回循环和脾脏（FC） 介导的间隙。该技术允许独立定量 评估C3B和FC在A下介导的体内间隙途径 各种实验条件。乙醇的剂量范围 间隙以及缺陷的时间和持续时间，差异 在急性推注和慢性进食以及另一种小鼠菌株中的效果 将确定摄入乙醇的已知。选择性效果 补体介导的清除将通过增加的作用来确认 FC介导的间隙，通过 用眼镜蛇毒素因子治疗和使用小鼠菌株与 补体间隙中的遗传相对缺陷。相对数量的 功能性C3B受体和持续的速率控制其活性 将通过动力学技术在乙醇和对照小鼠中确定。这 假设选择性减少补体清除率是由于 乙醇代谢的产物对库普弗细胞的优先损害 将使用手术和动力学的组合检查肝细胞 技术以及选择性抑制乙醇中的步骤 与4-甲基吡唑和氰酰胺的代谢。 这些研究获得的知识应通过 哪种酒精可以充当传染性发展的辅助因子 疾病。