Natural Killer T Cells in an Animal Model of Hepatitis C

描述（由申请人提供）：虽然有大量关于丙型肝炎病毒（HCV）感染中常规T细胞的信息，但对肝脏中存在的其他细胞类型知之甚少，肝脏中含有大量不太常规的细胞，包括自然杀伤T（NK T）细胞。越来越多的证据表明，HCV感染早期免疫应答的失败与持续感染有关，但很少关注先天免疫，这可能是感染结果的关键。一个NKT细胞亚群，CD 1d反应性T细胞和配体CD 1d在哺乳动物进化中高度保守。这些细胞在保护性和病理性免疫应答的启动和控制中具有重要的调节作用。来自不同部位的CD 1d反应性NKT细胞的功能活性显著不同，可能反映了不同的生理作用。虽然骨髓来源的CD 1d反应性NK T细胞产生大量抗炎细胞因子，但慢性HCV患者的相应肝脏群体具有相反的促炎极性。值得注意的是，相当一部分人肝内淋巴细胞（IHL）是CD 1d反应性NKT细胞。我们假设，NKT产生足够的IFN-？在急性感染期间，促进HCV的持续存在。由于在急性感染期间检查外周和肝室的能力是有限的，在HCV患者，我们建议检查CD 1d反应性NKT细胞在HCV的唯一动物模型，黑猩猩，感染前，期间和之后。为了实现这一点，我们将利用已经在AI 048231中研究的从黑猩猩获得的样品：1）确定在急性感染之前、期间和之后CD 1d反应性NK T细胞的频率和效应功能，以确定这些细胞是否存在功能损害; 2）确定NK T细胞是否在HCV肝炎的慢性期充当促炎细胞并促进肝损伤;和3）确定是否存在CD 1d反应性NK T细胞的区室化以及这种区室化的动力学。这些研究的结果与我们的合作者对AI 048231的常规免疫反应的表征协同作用，将帮助我们理解为什么HCV在大多数感染患者中持续存在，并可能提出新的治疗靶点。

DESCRIPTION (provided by applicant): While there is considerable information about conventional T cells in hepatitis C virus (HCV) infection, less is known about other cell types present within the liver, which contains large numbers of less conventional cells, including natural killer T (NK T) cells. There is mounting evidence that failure of the immune response early in HCV infection is associated with persistent infection, yet little attention has been paid to innate immunity, which is presumably critical to the outcome of infection. An NKT cell subset, CD1d-reactive T cells, and the ligand CD1d have been highly conserved across mammalian evolution. These cells have an important regulatory role in initiation and control of both protective and pathologic immune responses. The functional activities of CD1d-reactive NKT cells from various site is dramatically different, presumably reflective of distinct physiological roles. While bone marrow derived CD1d-reactive NK T cells produce large amounts of anti-inflammatory cytokines, the corresponding liver population in patients with chronic HCV has the opposite pro-inflammatory polarity. Remarkably, a substantial fraction of human intrahepatic lymphocytes (IHL) are CD1d-reactive NKT cells. We hypothesize that failure of NKT to produce adequate IFN-? during acute infection facilitates the persistence of HCV. Since the ability to examine both peripheral and liver compartments during acute infection is limited in patients with HCV, we propose to examine CD1d-reactive NKT cells in the only animal model of HCV, the chimpanzee, before, during, and after infection. To accomplish this, we will utilize samples obtained from chimpanzees already under study in AI048231 to: 1) determine the frequency and effector function of CD1d reactive NK T cells before, during and after acute infection to determine whether there is functional impairment of these cells; 2) determine whether NK T cells serve as pro-inflammatory cells in the chronic phase of HCV hepatitis and contribute to liver injury; and 3) determine whether there is compartmentalization of CD1d reactive NK T cells and the kinetics of this compartmentalization. Results of these studies, in synergy with the characterization of the conventional immune response by our collaborators on AI048231, will help us understand why HCV is persistent in the majority of infected patients and might suggest new therapeutic targets.