IMMUNITY TO HEPATITIS C IN LIVER TRANSPLANT RECIPIENTS

描述：（改编自申请人摘要）丙型肝炎病毒 (HCV)是美国终末期肝病的重要原因 在大多数移植中心， 移植 肝移植后，HCV病毒血症发生在 几乎100%的HCV感染者。 大约一半的感染者 肝移植受者将发展为临床上显著的肝炎， 在免疫功能正常的人中， 主持人 HCV感染的移植受者的一个子集可能具有快速移植 损失和受损的生存。 目前唯一获得许可的HCV治疗方法 感染，干扰素-α（IFN-α），具有低的持续反应率， 增加了同种异体移植受者慢性排斥反应的风险。 鉴于 HCV对移植受者的影响，需要更大的 了解这种感染的发病机制。 无论是病毒还是 定义了决定结果的宿主因素。 目前没有 HCV感染的小动物模型;因此， 受感染的个体对于理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宿主防御的重要组成部分， 在移植受者中减弱。 特别是细胞毒性T淋巴细胞 (CTL)是保护性宿主免疫的重要因素，但在 某些情况可能会导致宿主组织损伤而不清除病毒 感染 通过比较免疫功能正常的人和非免疫功能正常的人对HCV的免疫应答， 宿主和移植受体，可能会确定哪个宿主 因子在控制病毒血症中是重要的， 加速疾病的发生。 这项提案的目的是 了解细胞毒性T淋巴细胞在限制病毒感染中的作用 复制的 本建议的具体目标是：1）界定 移植受者中HCV特异性细胞免疫应答; 2） HCV特异性CTL应答谱与疾病活动性相关 在移植受者中;和3）表征细胞因子在 移植受者中HCV特异性CTL应答 这些研究将 为疫苗开发提供必要的科学背景 或免疫疗法。

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.