Effect of Chronic Alcohol Use on Alloimmunity.

 描述（由申请人提供）：在美国，用于治疗酒精诱导的慢性肝病（ALD）的原位肝移植（OLT）的需求超过了供体肝脏的可用性。在慢性酗酒者中奥尔特的资格需要6个月的清醒期。这个六个月的规则对于重度酒精性肝炎患者来说是有问题的 以及高的终末期肝病模型（MELD）评分，因为死亡风险在这6个月内。使用肝细胞（肝细胞）的细胞替代疗法（CRT）已被认为是一种短期的肝脏支持，直到获得合适的肝脏，并且急性或慢性肝功能衰竭的几项临床前和临床研究已经证明，肝细胞CRT可以支持肝功能并改善小鼠和患者的存活率。然而，这种疗法的一个重要障碍是免疫排斥，这主要是由T细胞依赖性途径介导的。在免疫功能正常的移植受者中，需要免疫抑制药物来防止移植排斥反应。来自酒精研究的证据表明，酒精消耗可能会降低免疫功能，从而减少肝脏或肝细胞移植后的排斥反应。这一观察结果的潜在机制仍然没有答案。一些研究表明，长期饮酒导致T细胞淋巴细胞减少症，这反过来又诱导记忆样T细胞的抗原非依赖性扩增，称为稳态增殖。这些事件是否直接导致免疫抑制仍然没有答案，尽管我们相信这些事件可能与过早的免疫衰老和细胞衰老有关。因此，本研究的长期目标是检验长期饮酒加速T细胞老化和损害T细胞功能，从而减少T细胞介导的移植物损伤的假设 ALD患者在CRT和奥尔特后需要较少的免疫抑制。为了验证这一假设，我提出了两个目标：在第一个目标中，我将描述慢性乙醇消耗对T细胞功能和衰老的影响，并确定这些对T细胞的影响在乙醇戒断后是否可逆。在第二个目标中，我将使用慢性酒精小鼠模型来确定与移植到无乙醇对照中的肝细胞相比，移植的肝细胞是否具有改善的移植物存活，并将评估慢性酒精消耗对T细胞同种免疫的影响。这项研究的结果将对公众健康产生多重影响。他们将：1）确定慢性酒精消耗对T细胞免疫应答的影响，2）评估肝细胞移植后慢性酒精模型中受损的T细胞功能，3）提供在ALD患者中使用降低水平的免疫抑制药物进行CRT的证据，和4）为具有高MELD评分的个体和已停止饮酒并正在努力戒酒的患者提供潜在的治疗策略，或者已经清醒6个月但正在等待奥尔特。

 DESCRIPTION (provided by applicant): The need for orthotopic liver transplantation (OLT) for the treatment of alcohol induced chronic liver disease (ALD) in the US outnumbers the availability of donor livers. Eligibility for OLT amongst chronic alcoholics requires a 6-months period of sobriety. This six-month rule is problematic for patients with severe alcoholic hepatitis and a high model for end-stage liver disease (MELD) score, as the mortality risk is within this 6-month period. Cell replacement therapy (CRT) using liver cells (hepatocytes), has been considered as a short-term liver support until a suitable liver is available, and several preclinicl and clinical studies of acute or chronic liver failure have demonstrated that hepatocyte CRT can support liver function and improve survival in mice and in patients. A significant barrier to this therapy, however, is immunological rejection, which is largely mediated by a T cell-dependent pathway. In immunocompetent transplant recipients, immunosuppressive drugs are required to prevent transplant rejection. Evidence from alcohol research suggests ethanol consumption may diminish immune function resulting in reduced rejection following liver or hepatocyte transplantation. The underlying mechanism for this observation remains unanswered. Some studies suggest chronic alcohol consumption leads to T cell lymphopenia, which in turn induces antigen-independent expansion of memory-like T cells, termed homeostatic proliferation. Whether these events directly contribute to immunosuppression remains unanswered, although we believe these events may be linked to premature immune aging and cellular senescence. Thus, the long-term objective of this study is to test the hypothesis that chronic alcohol use accelerates T cell aging and impairs T cell function, thereby reducing T cell mediated graft injury and necessitating less immunosuppression after CRT and OLT for individuals with ALD. To test this hypothesis, I propose two Aims: in the First Aim I will characterize the effect of chronic ethanol consumption on T cell function and aging, and determine if these effects on T cells are reversible following ethanol withdrawal. In the Second Aim I will use a chronic alcohol mouse model to determine whether transplanted hepatocytes have improved graft survival compared to hepatocytes transplanted into ethanol free controls, and will evaluate the effect of chronic alcohol consumption on T cell alloimmunity. The findings from this study will have multiple impacts on public health. They will: 1) define the impact of chronic ethanol consumption on T cell immune responses, 2) assess impaired T cell function in a chronic alcohol model following hepatocellular transplantation, 3) provide evidence for using reduced levels of immunosuppressive drugs for CRT in patients with ALD, and 4) provide a potential treatment strategy for individuals with a high MELD score and for patients who have stopped drinking and are working towards sobriety, or have been sober for 6 month but are awaiting OLT.