Natural Killer T Cells in an animal model of hepatitis C

描述（由申请人提供）：虽然关于丙型肝炎病毒（HCV）感染中的常规T细胞有相当多的信息，但对肝脏中存在的其他细胞类型知之甚少，其中包含大量非常规细胞，包括自然杀伤T （NK T）细胞。越来越多的证据表明，HCV感染早期免疫反应的失败与持续感染有关，但人们很少关注先天免疫，而先天免疫可能对感染的结果至关重要。NKT细胞亚群，CDld反应性T细胞和配体CDld在哺乳动物进化过程中高度保守。这些细胞在保护性和病理性免疫反应的启动和控制中具有重要的调节作用。不同部位的cdld反应性NKT细胞的功能活动有显著差异，可能反映了不同的生理作用。虽然骨髓来源的cdld反应性NK T细胞产生大量的抗炎细胞因子，但慢性HCV患者相应的肝脏群体具有相反的促炎极性。值得注意的是，人类肝内淋巴细胞（IHL）的很大一部分是cdld反应性NKT细胞。我们假设NKT在急性感染期间不能产生足够的ifn - γ有助于HCV的持续存在。由于HCV患者在急性感染期间检测外周和肝室的能力有限，我们建议在唯一的HCV动物模型黑猩猩中检测ccdd反应性NKT细胞，在感染之前，期间和之后。为了实现这一目标，我们将利用已经在AI048231研究中获得的黑猩猩样本：1)确定CD1d反应性NK T细胞在急性感染之前，期间和之后的频率和效应功能，以确定这些细胞是否存在功能损伤；2)确定NKT细胞是否在HCV肝炎慢性期起促炎细胞作用并参与肝损伤；3)确定CDld反应性NK T细胞是否存在区隔化以及这种区隔化的动力学。这些研究的结果，与我们的合作者对AI048231的传统免疫反应的描述协同作用，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, CDld-reactive T cells, and the ligand CDld 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 CDld-reactive NKT cells, from various sites, are dramatically different, presumably reflective of distinct physiological roles. While bone marrow derived CDld-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) is CDld-reactive NKT cells. We hypothesize that failure of NKT to produce adequate IFN-gamma 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 CDld-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 NKT 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 CDld 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.