IMMUNE RESPONSE TO ACETALDEHYDE ADDUCTS ON LIVER CELLS

肝细胞上乙醛加合物的免疫反应

• 批准号: 3111739
• 负责人: LYNELL W. KLASSEN
• 金额: $ 10.58万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-04-01 至 1992-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3111739
• 关键词: acetaldehyde; adduct; alcoholic beverage consumption; alcoholic fatty liver; alcoholic hepatitis; alcoholic liver cirrhosis; alcoholism /alcohol abuse; antibody; antibody specificity; cell mediated cytotoxicity; cellular immunity; drug adverse effect; drug metabolism; enzyme linked immunosorbent assay; helper T lymphocyte; hybridomas; immunological substance; immunoregulation; laboratory mouse; liver cells; membrane proteins; monoclonal antibody; radionuclides; suppressor T lymphocyte; surface antigens; tissue /cell culture

Alcoholic liver disease remains a major worldwide health problem. Although many varied pathogenic mechanisms have been implicated in the development of ethanol-induced hepatocellular damage, recent studies suggest that the immune system may play a key role in the initiation or maintenance of liver damage. This project will study the hypothesis that alcohol metabolized to acetaldehyde complexes with liver cell membrane proteins forming stable acetaldehyde adducts. These acetaldehyde-protein adducts may act as antigens, inducing an immune response characteristic of autoimmune phenomenon. Furthermore, acute or chronic ingestion of alcohol itself may alter the immune response to acetaldehyde-surface protein epitopes. The specific aims are: 1) To develop a panel of polyclonal and monoclonal antibodies that recognize epitopes on acetaldehyde-modified liver cell membrane surfaces, including antibodies directed against acetaldehyde adducts on intact liver cell culture line. 2) Develop antibodies that uniquely recognize epitopes on acetaldehyde-modified proteins formed under reducing versus non-reducing conditions. 3) Demonstrate the presence of acetaldehyde-modified surface antigens on intact liver cells by direct binding of antibodies to liver cell culture line; by in situ binding of antibodies to murine liver cells modified by in vivo alcohol feeding; by detection of anti-acetal dehyde/liver surface membrane adducts by using a B lymphocyte in vitro culture system. The role of the T helper and T suppressor cells in regulating this immune response to acetal dehyde- surface membrane adducts by using a B lymphocyte in vitro culture system. The role of T helper and T suppressor cells in regulating this immune response will be defined. In addition, the effect of in vivo ethanol feeing on the immunoregulatory subpopulations will be studied. The immunoregulatory requirements of anti-acetal dehyde-membrane antibody production noted in vitro will be confirmed by in vivo depletion of selective lymphocyte subsets utilizing adult thymectomy and in vivo monoclonal antibody administration.

酒精性肝病仍然是全球主要的健康问题。 虽然 许多多种致病机制与发育有关 最近的研究表明，乙醇引起的肝细胞损伤 免疫系统可能在肝脏的启动或维持中起关键作用 损害。 该项目将研究酒精代谢为 用肝细胞膜蛋白形成稳定的乙醛复合物 乙醛加合物。 这些乙醛蛋白加合物可能充当 抗原，诱导自身免疫的免疫反应特征 现象。 此外，急性或长期摄入酒精本身可能 改变对乙醛表面蛋白表位的免疫反应。 这 具体目的是：1）开发一个多克隆和单克隆面板 识别乙醛改性肝细胞上表位的抗体 膜表面，包括针对乙醛的抗体 完整的肝细胞培养线上的加合物。 2）开发抗体 独特地识别在乙醛改性蛋白上的表位 减少与非还原条件。 3）证明存在 乙醛改性的表面抗原在完整的肝细胞上直接 抗体与肝细胞培养线的结合；通过原位结合 通过体内酒精摄入修饰的鼠肝细胞的抗体；经过 通过使用A B淋巴细胞在体外培养系统中。 T助手和T的作用 抑制细胞在调节这种免疫反应中对乙酰脱氢的反应 通过在体外培养系统中使用B淋巴细胞的表面膜加合物。 T助手和T抑制细胞在调节这种免疫中的作用 响应将被定义。 另外，体内乙醇的作用 将研究免疫调节亚群的费用。 这 抗乙酰脱氢脱氢抗体的免疫调节要求 体外耗竭将确认体外的生产 使用成人胸腺切除术和体内的选择性淋巴细胞亚群 单克隆抗体给药。