ANTIGENICITY OF PROTEINS MODIFIED BY ALCOHOL METABOLITES

酒精代谢物修饰的蛋白质的抗原性

基本信息

批准号：
6168184
负责人：
Monte S Willis
金额：
$ 2.57万
依托单位：
UNIVERSITY OF NEBRASKA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-04-01 至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/6168184
关键词：
adduct alcohol dehydrogenase alcoholic beverage consumption antigens cell type drug interactions humoral immunity intermolecular interaction laboratory mouse malonaldehyde protein metabolism protein transport tissue /cell culture

项目摘要

It has been shown that long term alcohol ingestion can lead to the development of chemical changes to proteins. It is believed that metabolism of alcohol by alcohol dehydrogenase to acetaldehyde (AA) and lipid peroxidation of polyunsaturated fats to malondialdehyde (MDA) results in the adduction of proteins with both of these aldehyde species. In fact, AA and MDA have been shown to react in a synergistic manner to form a distinct adduct (MAA) that has been found in in vitro as well as in vivo experimentally. This MAA adduct has been shown to induce a strong antibody response to both the MAA epitope(s) and to the carrier protein without the use of adjuvants. We hypothesize that following chronic ethanol consumption MAA-modified proteins induce and unique immune response to the MAA-epitope, as well as, to nonmodified epitopes on soluble carrier proteins. The ability of MAA-modified soluble proteins to induce and immune response is dependent on unique features of antigen processing antigen presentation, and mechanisms of T-cell immunoregulatory circuits. The principal objective of this research project is to define and characterize the humoral and cellular immune responses to MAA-adducted proteins. To determine the cell types primarily involved in the uptake, processing and presentation of proteins modified by MAA and assess whether these immune mechanisms play a role in the development and/or progression of alcohol liver disease. We propose to address the effects of chronic ethanol consumption on these problems using the following specific aims: 1) Characterize the ability if MAA adducted proteins to induce and antibody (humoral immune) response without adjuvant to the MAA epitopes on soluble proteins; 2)Characterize the T cell response to MAA adducted soluble proteins following immunization; 3) Determine the cell types that are involved in the uptake, processing, and presentation of MAA-adducted proteins.

研究表明，长期饮酒会导致蛋白质发生化学变化。据信酒精通过乙醇脱氢酶代谢为乙醛（AA）多不饱和脂肪脂质过氧化生成丙二醛（MDA）导致蛋白质与这两种醛类加合。事实上，AA 和 MDA 已被证明能够以协同方式发生反应，形成一种独特的加合物 (MAA)，该加合物已在体外和体外发现体内实验。这种 MAA 加合物已被证明可以诱导对 MAA 表位和载体都有强烈的抗体反应不使用佐剂的蛋白质。我们假设长期使用 MAA 修饰的乙醇后蛋白质还可诱导针对 MAA 表位的独特免疫反应例如，可溶性载体蛋白上的未修饰表位。的能力 MAA 修饰的可溶性蛋白诱导和依赖免疫反应关于抗原加工抗原呈递的独特特征，以及 T 细胞免疫调节回路的机制。该研究项目的主要目标是定义和表征对 MAA 加合体的体液和细胞免疫反应蛋白质。为了确定主要参与吸收的细胞类型， MAA 修饰的蛋白质的加工和表达并评估这些免疫机制是否在发育和/或酒精肝病的进展。我们建议解决影响使用以下方法来评估长期乙醇消耗对这些问题的影响具体目标： 1) 表征 MAA 加合蛋白质的能力无需 MAA 佐剂即可诱导抗体（体液免疫）反应可溶性蛋白质上的表位； 2)表征T细胞对MAA的反应免疫后加合可溶性蛋白质； 3）确定小区参与吸收、处理和呈现的类型 MAA 加合蛋白。