THE ROLE OF IMMUNE RESPONSES IN ALCOHOLIC LIVER DISEASE

描述（由申请人提供）：研究表明，饮酒与抑制对感染因子的免疫反应有关。 免疫应答，特别是细胞介导的免疫应答的抑制导致对包括嗜肝细菌和病毒的感染因子的易感性增加。 在我的实验室进行的研究表明，无论是Lieber DeCarli还是更慢性的ETOH水方案，小鼠饮酒都会导致无法控制鼠巨细胞病毒（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IFN-γ产生减少）。 在本申请中将解决的假设是，小鼠的慢性酒精消耗影响感染早期和肝脏中对嗜肝病毒的先天性和获得性免疫应答的诱导，最终导致消耗酒精的小鼠中更大和更长时间的肝脏感染。 肝脏中病毒数量的增加导致NK细胞和CD 8 + T细胞在肝脏中的长期（慢性）积累，这介导了长期的肝损伤。 还假设所描述的与小鼠慢性饮酒相关的CD 8 + T细胞的非特异性活化导致介导肝细胞杀伤的活化的CD 8 + T细胞在肝脏中的积累。 通过以下具体目标来进行机制研究以解决这些假设：1.确定饮用水中的乙醇方案的酒精消耗对病毒抗原特异性CD 8 + T细胞的产生和抗原特异性CD 8 + T细胞向肝脏的运输的影响。 2.确定长期饮酒对接种DNA疫苗诱导的MCMV细胞和体液免疫应答的影响，DNA疫苗包含主要和次要I类MHC限制性表位以诱导CD 8 + T细胞，完整病毒疫苗诱导抗体应答。 3.确定饮酒对MCMV先天性应答的影响，这将影响抗原特异性CD 8 +T细胞的产生。 4.目的探讨NK细胞在酒精性小鼠巨细胞病毒（MCMV）感染性肝炎中的作用。

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.