KILLER CELLS AND ALCOHOL

描述（由申请人提供）：长期饮酒与某些感染（包括结核病）、自身免疫性疾病和某些恶性肿瘤的发病率增加有关。旨在了解免疫系统这种明显不利调节的潜在机制的研究发现先天免疫和适应性免疫都存在异常。由于缺乏纵向研究和酒精性肝病引入的复杂因素，人类免疫学研究受到阻碍。慢性乙醇（ETOH）摄入的动物模型可以检查ETOH摄入的剂量和持续时间对各种免疫功能的影响。最近开发了一种安全有效的小鼠长期ETOH给药方案，并将用于本申请。最近的发展强调了先天免疫的重要性，不仅在早期防御，而且在适应性免疫反应的类型和幅度的调节。天然杀伤（NK）和NKT细胞是先天免疫的主要成分，通过其细胞毒性活性以及通过其产生细胞因子的能力影响下游免疫应答。基于初步数据，本申请的假设是ETOH对NK细胞应答具有双相效应，早期抑制随后增强活性。相反，ETOH似乎对NKT细胞具有持续的抑制作用。乙醇对这些活性的净效应可能是由于对细胞本身的直接效应以及已知调节其活性的间接效应（例如I类MHC表达、前列腺素合成、细胞因子、细胞因子受体和树突状细胞（DC））的组合。这些机制，以及它们在体内的相关性，将被检查。初步数据表明，ETOH对先天免疫的影响超出了其对基线活性的影响。分枝杆菌DNA及其片段是一种强有力的免疫刺激剂，对CpG寡脱氧核苷酸（ODN）的开发有重要影响。由于分枝杆菌感染在酗酒者中的发病率很高，一种假设是ETOH减弱了对分枝杆菌DNA的反应。初步数据提示ETOH减弱了CpG ODN诱导的NK活性增强

DESCRIPTION (provided by applicant): Chronic alcohol consumption is associated with increased incidence of certain infections (including tuberculosis), autoimmune diseases, and certain malignancies. Studies aimed at understanding the underlying mechanisms of this apparent adverse modulation of the immune system have found abnormalities in both innate and adaptive immunity. Immunological studies in humans have been hampered by the lack of longitudinal studies and by the complicating factors introduced by alcoholic liver disease. Animal models of chronic ethanol (ETOH) ingestion can afford the luxury of examining the effect of the dose and duration of ETOH ingestion on various immune functions. A safe and effective protocol for chronic ETOH administration in mice has been recently developed and will be utilized in this application. Recent developments have highlighted the importance of innate immunity not only in early defenses but also in the regulation of the type and magnitude of adaptive immune responses. Natural killer (NK) and NKT cells, major components of innate immunity, influence downstream immune responses both by their cytotoxic activity as well as by their ability to elaborate cytokines. Based on preliminary data, the hypothesis of this application is that ETOH has a biphasic effect on NK cell responses with an early inhibition followed by enhanced activities. In contrast, it appears ETOH has a persistent inhibitory effect on NKT cells. The net effect of ethanol on these activities may be due to a combination of a direct effect on the cells themselves as well as indirect effects known to modulate their activity such as Class I MHC expression, prostaglandin synthesis, cytokines, cytokine receptors, and dendritic cells (DC). These mechanisms, and their in vivo relevance, will be examined. Preliminary data indicate that the effect of ETOH on innate immunity extends beyond its effect on the baseline activity. Mycobacterial DNA and DNA fragments are potent immunostimulatory agents and were the influence for the development of CpG oligodeoxynucleotides (ODN). Since mycobacterial infections are seen in a high incidence rate in alcoholics, one hypothesis is that ETOH blunts the response to mycobacterial DNA. Preliminary data prompted the hypothesis that ETOH blunts the enhanced NK activity induced by CpG ODN