ALCOHOL AND THE DEVELOPMENT OF NATURAL KILLER CELLS

胎儿酒精综合征(FAS)儿童存在宿主防御缺陷和 随之而来的是威胁生命的感染发生率的增加。 一些患有自闭症的儿童在体液和体液两方面长期存在缺陷 细胞免疫，表明宫内酒精暴露 可能会干扰免疫发展中的关键事件 系统。自然杀伤(NK)细胞，淋巴细胞的一个亚群 与T细胞和B细胞不同，已被证明能介导 免疫中的效应器、调节和发育事件的数量 系统。NK细胞是宿主防御的重要组成部分 微生物(包括病毒和细菌)感染和宿主 抵抗肿瘤生长和转移。由于NK细胞具有功能 在人类出生时，体液和细胞介导的系统仍然 这些未成熟的效应细胞可能对 婴儿对感染的抵抗力。免疫的成熟 小鼠的反应也是年龄相关的，因为功能正常的NK细胞 直到小鼠断奶的时候才发育提供极好的 研究这些效应细胞发育的模型。这是众所周知的 然而，血液中高水平的酒精会抑制NK细胞。 不知道酒精暴露是在宫内还是在新生儿中 周期(通过母乳喂养)影响自然杀伤细胞的发育。在这 建议我们将确定乙醇的影响，在 不同发育阶段对NK细胞功能的影响。我们会 利用涉及交叉培养策略的小鼠模型 使小鼠在发育的不同阶段接触乙醇，以及 配对喂养和坚固的食物控制。我们建议确定什么影响 宫内和/或新生儿接触乙醇对：1)动力学 用流式细胞术测定新生儿NK细胞获得率 使用针对NK细胞的单抗。2)发展 NK功能，由肿瘤靶细胞的体外裂解和 NK祖细胞对生物反应的应答能力 修饰符。3)观察到的NK细胞功能变化的程度 体外反映这些细胞调节肿瘤细胞生长的能力 活着。实验小组的设计将使我们能够将 实验性暴露对NK细胞功能影响的观察 动物对乙醇的反应，并评估任何影响的持久性(成人 动物)宫内和/或新生儿体内酒精暴露 NK功能。因为饮食可能会引起 我们在实验设计中注意到的测量参数 包括允许我们将酒精的影响从 任何饮食都会引起改变。确定母婴传播的后果 酒精摄入量和新生儿酒精暴露对发育的影响 免疫系统是理解基础的必不可少的深刻的 一些患有Fas的儿童表现出免疫缺陷。此外，由于 越来越多的女性在酗酒的同时滥用药物 研究对婴儿出生的健康有重大影响 对艾滋病高危人群中的妇女。

Fetal alcohol syndrome (FAS) children have defects in host defense and a concomitant increase in the incidence of life threatening infections. Some children with FAS have long lasting deficiencies in both humoral and cell mediated immunity, suggesting that interuterine exposure to alcohol may interfere with critical events in the development of the immune system. Natural killer (NK) cells, a subset of lymphocytes distinguishable from both T and B cells, have been shown to mediate a number of effector, regulatory, and developmental events in the immune system. NK cells constitute an important component of host defense to microbial (both viral and bacterial) infections as well as host resistance to tumor growth and metastasis. Since NK cells are functional at birth in humans, while the humoral and cell mediated systems are still immature, these effector cells may be particularly important to the infant for the resistance to infection. The maturation of the immune response in the mouse is also age dependent and since functional NK cells do not develop until the time of weaning the mouse provides an excellent model for studying the development of these effector cells. It is known that high blood levels of alcohol can inhibit NK cells, however, it is not known whether or not alcohol exposure in utero or in the neonatal period (via breast feeding) affects the development of NK cells. In this proposal we will determine the effects of ethanol, administered at different stages in development, on the function of NK cells. We will utilize a mouse model which involves the strategy of cross-fostering to expose mice to ethanol at different stages of development, along with pair fed and solid food controls. We propose to determine what effects interuterine and/or neonatal exposure to ethanol have on: 1) the kinetics of neonatal acquisition of NK cells, as determined by flow cytometry using monoclonal antibodies specific for NK cells. 2) the development of NK function, as determined by in vitro lysis of tumor target cells and the capacity of NK progenitors to respond to biological response modifiers. 3) the extent to which changes observed in NK cell function in vitro reflect the ability of these cells to regulate tumor cell growth in vivo. The design of experimental groups will allow us to attribute observed changes in NK cell function to the exposure of the experimental animals to ethanol and to assess the persistence of any effect (in adult animals) of interuterine and/or neonatal exposure to alcohol on in vivo NK function. Because of the potential that diet may induce changes in the measured parameters we have taken care in the experimental design to include groups which will allow us to isolate the effects of alcohol from any diet induced changes. Establishing the consequences of maternal alcohol consumption and neonatal exposure to alcohol on the developing immune system is essential for understanding the basis for the profound immunodeficiency exhibited by some children with FAS. Furthermore, since an increasing number of woman abuse drugs along with alcohol, this research has significant implications in the well being of infants born to women in the population at high risk for AIDS.