RE-ESTABLISHMENT OF IMMUNITY IN ALCOHOL-CONSUMING MICE

饮酒小鼠免疫力的重建

基本信息

批准号：
2330142
负责人：
CARL WALTENBAUGH
金额：
$ 16.99万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1995
资助国家：
美国
起止时间：
1995-02-01 至 1999-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/2330142
关键词：
acetylcysteine alcoholic beverage consumption antigen presenting cell biological response modifiers biological signal transduction cellular immunity copolymer I disease /disorder model ethanol flow cytometry glutathione humoral immunity laboratory mouse lymphocyte lymphokines macrophage synthetic enzyme

项目摘要

Excessive alcohol consumption is a major threat to human health. Normal host defense mechanisms are compromised in alcoholic patients, often resulting in pronounced frequency and severity of infections. Both clinical and experimental evidence suggest that alcohol alters the immune system. Chronic alcohol consumption impairs induction of human cell- mediated immune responses and elevates serum antibody levels. A mouse model employing synthetic copolymer antigens shows that ethanol enhances poly(Glu/50Tyr/50) (GT)-specific humoral immunity and impairs poly(Glu/60Ala/30Tyr/10)(GAT)-specific cell-mediated immunity regulated by CD-4 bearing helper (Th) lymphocytes designated Th2 and Th1, respectively. Despite its impact upon defense, little is known of how ethanol alters immune function. Other agents which alter immune function, such as cyclophosphamide and gamma-irradiation, provide a common thread with ethanol in that all deplete the intracellular thiols cysteine and glutathione (GSH). T cells have extremely weak cystine transport activity and cannot make cysteine. T cell function is exquisitely sensitive to intracellular GSH depletion. Intracellular thiols inhibit the activation of nuclear factor-kappaB (NF-kappaB), a T cell transcription factor, a factor that also controls replication of human immunodeficiency virus (HIV). Chronic ethanol consumption may increase susceptibility to HIV infection for those individuals at risk. Clinically, N-acetyl-L-cysteine (NAC) is administered to replenish GSH levels. Both cysteine and NAC inhibit the activation of NF-kappaB and also inhibit the replication of HIV which is under transcriptional control of NF-kappaB. Our preliminary findings show that oral administration of NAC restores GAT-specific cell- mediated immune function delayed hypersensitivity) to ethanol-consuming C57BL/6 mice and causes a marked decrease in serum alcohol concentrations. We propose to direct the activities of our laboratory toward three major goals; 1) The effect of glutathione replenishment using NAC and related compounds on cell-mediated (GAT) and humoral immune (GT) responses in ethanol-consuming mice. 2) Identify which cells of the immune system, lymphocytes or macrophages, are most affected by glutathione depletion/repletion. 3) Identify how cells of the immune system are affected (e.g., antigen presentation, signal transduction, lymphokine production) when depleted of GSH by ethanol and when glutathione is replenished. This exciting finding may lend significant insights into the mechanism(s) of immune alteration by ethanol and may offer strategies to minimize risk to alcoholics of HIV infection and other infectious organisms.

过度饮酒是对人类健康的主要威胁。普通的酒精患者通常会损害宿主防御机制导致感染的明显频率和严重程度。两个都临床和实验证据表明酒精会改变免疫系统。长期饮酒会损害人类细胞的诱导介导的免疫反应并提高血清抗体水平。鼠标采用合成共聚物抗原的模型表明乙醇增强 poly（GLU/50TYR/50）（GT） - 特异性的体液免疫和损害 poly（GLU/60ALA/30TYR/10）（GAT）特异性细胞介导的免疫，由受调节的免疫力 CD-4轴承辅助器（Th）淋巴细胞分别指定为Th2和Th1。尽管它对防御的影响，但对乙醇的改变知之甚少免疫功能。其他改变免疫功能的药物，例如环磷酰胺和γ-辐照，提供了一个共同的线乙醇耗尽了细胞内硫醇半胱氨酸和谷胱甘肽（GSH）。 T细胞的胱氨酸转运活性极为弱并且不能制作半胱氨酸。 T细胞功能对细胞内GSH耗竭。细胞内硫醇抑制活化核因子-kappab（NF-kappab），T细胞转录因子，A 还控制人类免疫缺陷病毒复制的因素（艾滋病病毒）。慢性乙醇消耗可能会增加对艾滋病毒的敏感性那些有危险的人的感染。临床上，N-乙酰基-L-半胱氨酸（NAC）用于补充GSH水平。半胱氨酸和NAC 抑制NF-kappab的激活，并抑制复制 HIV受NF-kappab的转录控制。我们的初步调查结果表明，NAC的口服给药恢复了GAT特异性细胞 - 介导的免疫功能延迟了超敏反应）至乙醇消费 C57BL/6小鼠，并导致血清酒精浓度显着降低。我们建议将实验室的活动引向三个主要目标； 1）使用NAC和相关的谷胱甘肽补充的效果细胞介导的（GAT）和体液免疫（GT）反应的化合物乙醇消费小鼠。 2）确定免疫系统的哪些细胞，淋巴细胞或巨噬细胞受到谷胱甘肽的影响最大耗尽/补充。 3）确定免疫系统的细胞如何受影响（例如，抗原表现，信号转导，淋巴因子生产）当乙醇耗尽GSH时，谷胱甘肽是补充。这一激动人心的发现可能会为乙醇免疫改变机制，并可能提供策略最大程度地降低艾滋病毒感染和其他感染性的酗酒者的风险有机体。