IMMUNE RESPONSES AND ACHOHOLIC LIVER DISEASE

描述：(改编自《调查者摘要》)酒精性肝病(ALD)是酒精滥用的严重后果，在美国导致大量的发病率和死亡率。ALD的发病机制尚不清楚，目前尚不清楚ALD的易感性与哪些因素有关。流行的观点是，某些因素在肝脏中启动了一种不受控制的炎症反应，最终导致了与此过程相关的特征性纤维化。来自该实验室的数据表明，在特定抗原或刀豆蛋白A激活T淋巴细胞后，可在乙醇(Etoh)喂养的C57BL/6小鼠中启动类似ALD事件序列的情况。这些激活刺激仅在Etoh喂养的小鼠中诱导脂肪变性和肝炎，最终导致肝脏损伤，以血清ALT和AST水平升高为证据。这些数据支持我们的观点，即至少有一个因素参与了ALD的发生和发展，这是肝脏中的一种特异性免疫反应。为了验证这一假设，我们建议使用ALD的这些小鼠模型和病毒性肝炎的模型来确定这种免疫介导的肝损伤的机制。我们的特定假设是，炎症过程的启动是特异性T细胞介导的杀伤的结果，要么是通过直接的细胞毒性作用，要么是通过感染肝细胞产生细胞毒性细胞因子。此外，我们假设与乙醇消耗相关的皮质类固醇的产生在这个系统中有双重影响。首先，免疫反应受到皮质类固醇的抑制，抑制了控制感染剂复制的能力，导致更多的炎症。其次，皮质类固醇通过直接T细胞介导的裂解或肿瘤坏死因子等炎性细胞因子介导的裂解，使肝细胞变得敏感，从而加强对这些细胞的破坏。这项拟议的研究还将确定启动或介导肝损伤的特定细胞，以及炎症反应和炎性细胞因子在这些实验性ALD模型中的作用。

DESCRIPTION: (Adapted from the Investigator's Abstract) Alcoholic liver disease (ALD) is a serious consequence of alcohol abuse and results in a great deal of morbidity and mortality in the United States. The mechanisms that lead to ALD are poorly understood, and it is not known what factors are involved in the susceptibility for the development of ALD. The prevailing opinion is that some factor initiates an inflammatory response in the liver that is uncontrolled and ultimately results in the characteristic fibrosis associated with this process. Data from this laboratory have shown that a condition that resembles the sequence of events in ALD can be initiated in ethanol (ETOH)-fed C57Bl/6 mice after activation of T-lymphocytes by specific antigen or concanavalin A. These activation stimuli induce steatosis and hepatitis only in ETOH-fed mice, which ultimately result in liver damage evidenced by elevated serum levels of ALT and AST. These data support our suggestion that at least one factor involved in initiation and development of ALD is a specific immune response in the liver. To test this hypothesis we propose to use these murine models of ALD and a model of viral hepatitis to define the mechanisms responsible for this immune - mediated liver damage. It is our specific hypothesis that initiation of the inflammatory process is the result of specific T cell-mediated killing, either through direct cellular cytotoxicity or through the production of cytotoxic cytokines of the infected hepatocyte. Further, we hypothesize that corticosteroid production associated with ETOH consumption has a twofold effect in this system. First, the immune response is suppressed by corticosteroids to inhibit the ability to control the replication of the infectious agents, results in more inflammation. Second, corticosteroids sensitizes hepatocytes to enhance destruction of these cells by either direct T-cell-mediated lysis or lysis mediated by inflammatory cytokines such as tumor necrosis factor. The proposed research will also define the specific cells that initiate or mediate liver damage as well as the role of the inflammatory response and inflammatory cytokines in these models of experimental ALD.