IMMUNITY TO HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS

描述：(改编自申请人的摘要)丙型肝炎病毒 (丙型肝炎病毒)是美国终末期肝病的重要原因 在各州，在大多数移植中心是一个主要的适应症 移植。肝移植后，丙型肝炎病毒血症发生在 几乎100%的丙型肝炎病毒感染者。大约一半的感染者 肝移植受者会患上临床上有意义的肝炎， 在免疫活性方面，哪一种肝炎的进展比丙型肝炎更快 主持人。一部分感染丙型肝炎病毒的移植受者可能有快速移植物 损失和生存受损。目前唯一获得批准的丙型肝炎病毒治疗方法 感染，干扰素-α(干扰素-a)，持续应答率低， 增加同种异体移植受者发生慢性排斥反应的风险。给定 丙型肝炎病毒对移植受者的影响，需要更大的 对该病发病机制的认识。既不是病毒也不是 定义了决定结果的主机因素。目前，还没有 丙型肝炎病毒感染的小动物模型；因此检查宿主的反应 感染者对于了解宿主的可能作用至关重要。 决定临床结果的因素。细胞免疫反应是一种 在大多数病毒感染中是宿主防御的关键组件，并且 在移植受者中减弱。尤其是细胞毒性T淋巴细胞 (CTL)是保护性宿主免疫的重要元素，但在 某些情况下可能会在未清除病毒的情况下导致宿主组织损伤 感染。通过比较丙型肝炎病毒的免疫应答在免疫活性上的差异 宿主和移植接受者，有可能确定哪一个宿主 控制病毒血症的因素是重要的，哪些宿主因素可能是 对加速疾病负有责任。这项提议的目标是 了解细胞毒性T淋巴细胞在限制病毒感染中的作用 复制。这项提案的具体目的是：1)界定 移植受者的丙型肝炎病毒特异性细胞免疫反应； 丙型肝炎病毒特异性CTL反应谱与疾病活动性的相关性 以及3)细胞因子在移植受者中的作用 移植受者的丙型肝炎病毒特异性CTL反应。这些研究将 为疫苗的开发提供必要的科学背景 或者免疫疗法。

DESCRIPTION: (Adapted from the applicant's abstract) Hepatitis C virus (HCV) is a significant cause of end stage liver disease in the United States, and in most transplant centers is a major indication for transplantation. Following liver transplantation, HCV viremia occurs in nearly 100% of HCV-infected individuals. Approximately half of infected liver transplant recipients will develop clinically significant hepatitis, which has a more rapid progression than HCV hepatitis in the immunocompetent host. A subset of HCV infected transplant recipients may have rapid graft loss and impaired survival. The only currently licensed therapy for HCV infection, interferon-alpha (IFN-a), has a low sustained response rate and increases the risk of chronic rejection in allograft recipients. Given the impact of HCV on transplant recipients, there is a need for a greater understanding of pathogenesis of this infection. Neither the viral nor the host factors which determine outcome are defined. At present, there is no small animal model for HCV infection; so examination of host responses in infected individuals is critical to understanding the possible role of host factors in determining clinical outcome. Cellular immune responses are a crucial component of host defenses in most viral infections and are attenuated in transplant recipients. In particular, cytotoxic T lymphocytes (CTL) are an important element of protective host immunity, but under certain circumstances may induce host tissue damage without clearing viral infection. By comparing the immune response against HCV in immunocompetent hosts and transplant recipients, it may be possible to determine which host factors are important in controlling viremia and which host factors may be responsible for accelerated disease. The goal of this proposal is understanding the role of cytotoxic T lymphocytes in limiting viral replication. The specific aims of this proposal are to: 1) define HCV-specific cellular immune responses in transplant recipients; 2) correlate the spectrum of HCV-specific CTL responses with disease activity in transplant recipients; and 3) characterize the role of cytokines in HCV-specific CTL responses in transplant recipients. These studies will provide the necessary scientific background for the development of vaccines or immunotherapies.