THE ROLE OF IMMUNE RESPONSES IN ALCOHOLIC LIVER DISEASE

描述(由申请人提供)：研究表明，饮酒与抑制对感染性病原体的免疫反应有关。免疫反应的抑制，特别是细胞免疫反应的抑制，导致对包括嗜肝细菌和病毒在内的感染性物质的易感性增加。在我的实验室所做的研究表明，无论是使用Lieber DeCarli还是使用更慢性的Etoh in water方案的小鼠，饮酒都会导致无法控制小鼠巨细胞病毒(MCMV)的感染，从而导致长期的肝脏感染和肝炎。饮酒也与对病毒的先天反应的改变有关(例如，IL-12和干扰素-伽马的产生减少)。在这一应用中将解决的假设是，小鼠长期饮酒影响在感染早期和肝脏对嗜肝病毒的先天和后天免疫反应的诱导，最终导致饮酒小鼠肝脏感染的程度更大、持续时间更长。肝脏中病毒数量的增加导致肝脏中NK细胞和CD8T细胞的长期(慢性)积聚，这导致了长期的肝脏损伤。还假设与小鼠慢性饮酒相关的CD8T细胞的非特异性激活导致激活的CD8T细胞在肝脏中积累，从而介导肝细胞的杀伤。解决这些假说的机制研究将通过解决以下具体目标来完成：1.确定饮酒和饮酒方案对病毒抗原特异性CD8T细胞的产生和抗原特异性CD8T细胞向肝脏的运输的影响。2.研究长期饮酒对MCMV诱导的细胞和体液免疫应答的影响。3.明确饮酒对MCMV先天免疫应答的影响，从而影响抗原特异性CD8T细胞的产生。4.明确NK细胞在饮酒小鼠巨细胞病毒感染所致肝炎中的作用。

DESCRIPTION (provided by applicant): Studies have shown that alcohol consumption is associated with a suppression of immune responses to infectious agents. The suppression of immune responses, especially cell-mediated immune responses, results in an increased susceptibility to infectious agents including hepatotropic bacteria and viruses. Studies done in my laboratory have shown that alcohol consumption by mice either with the Lieber DeCarli or with a more chronic ETOH in water protocol results in an inability to control the infection by murine cytomegalovirus (MCMV) that results in a prolonged liver infection and hepatitis. Alcohol consumption was also associated with alterations in innate responses to the virus (e.g., decreased IL-12 and IFN-gamma production). The hypothesis that will be addressed in this application is that chronic alcohol consumption by mice affects the induction of the innate and acquired immune responses to hepatotropic viruses early in the infection and in the liver that ultimately results in a greater and more prolonged hepatic infection in the mice that consume alcohol. This increase in viral numbers in the liver results in a prolonged (chronic) accumulation of NK cells and CD8+ T cells in the liver, which mediate prolonged liver damage. It is also hypothesized that the described nonspecific activation of CD8+ T cells associated with chronic alcohol consumption by mice results in accumulation of activated CD8+ T cells in the liver that mediate hepatocyte killing. Mechanistic studies to address these hypotheses will be done by addressing the following specific aims: 1.To define the effects of alcohol consumption with an ethanol in drinking water protocol on the production of viral antigen-specific CD8+ T cells and traffic of antigen-specific CD8+ T cells to the liver. 2. To define the effects of chronic consumption of alcohol on the induction of cellular and humoral immune responses to MCMV induced by vaccination with DNA vaccines that incorporate major and minor class I MHC-restricted epitopes to induce CD8+ T cells and an intact virus vaccine to induce antibody responses. 3. To define the effects of alcohol consumption on the innate responses to MCMV that would affect the production of antigen-specific CD8+T cells. 4. To define the role of NK cells in the hepatitis associated with MCMV infection of alcohol-fed mice.