IMMUNE RESPONSES AND ACHOHOLIC LIVER DISEASE

描述：（改编自研究者摘要）酒精性肝病（ALD）是酒精滥用的严重后果，在美国导致大量发病率和死亡率。导致ALD的机制尚不清楚，也不知道哪些因素与ALD的易感性有关。普遍的观点是，某些因素在肝脏中引发不受控制的炎症反应，并最终导致与此过程相关的特征性纤维化。本实验室的数据表明，在乙醇（ETOH）喂养的C57Bl/6小鼠中，在特定抗原或豆豆蛋白a激活t淋巴细胞后，可以引发类似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。血清ALT和AST水平升高，最终导致肝损伤。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，是肝脏的特异性免疫反应。为了验证这一假设，我们建议使用这些ALD小鼠模型和病毒性肝炎模型来确定这种免疫介导的肝损伤的机制。我们的具体假设是，炎症过程的启动是特异性T细胞介导的杀伤的结果，要么通过直接的细胞毒性，要么通过感染肝细胞产生细胞毒性细胞因子。此外，我们假设与ETOH消耗相关的皮质类固醇产生在该系统中具有双重作用。首先，免疫反应被皮质类固醇抑制，抑制了控制感染因子复制的能力，导致更多的炎症。其次，皮质类固醇使肝细胞增敏，通过直接t细胞介导的溶解或由炎症细胞因子（如肿瘤坏死因子）介导的溶解，增强肝细胞的破坏。本研究还将确定在这些实验性ALD模型中启动或介导肝损伤的特定细胞，以及炎症反应和炎症细胞因子的作用。

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.