Innate Immune Responses During Therapy for Chronic HCV

描述（由申请人提供）： 丙型肝炎病毒（HCV）是由丙型肝炎病毒引起的一种常见的传染病。尽管新疗法提高了持续应答率，但大多数患者对抗病毒治疗无效，仍有疾病进展的风险。在目前的提议中，由于病毒清除可能是由免疫应答的各种组分的有效协调介导的，我们将探索自然杀伤（NK）细胞和树突状细胞（DC）的相对贡献以及各种先天性细胞因子（例如，I型IFN、IL-15）。为了阐明先天性和适应性免疫应答的性质和动力学，以及它们如何在治疗环境中控制病毒复制，我们提出了三个具体目标，与NIDDK申办的Virahep-C抗病毒治疗耐药HCV临床研究合作完成。目标1.评价NK细胞应答对抗病毒治疗患者HCV控制的作用。我们假设，在基线时表现出NK细胞活性相对降低的患者对抗病毒治疗产生耐药性的可能性更大;此外，我们将研究治疗如何改变NK反应。目标二。确定髓样（mDC）和浆细胞样树突状细胞（pDC）的频率和功能如何与抗病毒治疗反应相关。病毒动力学应答（例如，无效应答对快速应答）将与DC的频率以及IFN-α和IL-12产生的水平相关。我们还将在体外和直接离体检查DC和NK细胞之间的免疫调节串扰。目标3.精确定义成功抗病毒治疗增强HCV特异性CD 8 + T细胞增殖的机制。HCV特异性CTL应答的成熟缺陷和功能损伤似乎可以用抗病毒治疗逆转，我们的初步数据表明先天性细胞因子（例如，IL-15）可能是关键。这些信息将提高我们对这种常见疾病的发病机制的理解，将提供生物标志物，用于识别更有可能在其病程早期对抗病毒治疗有反应或无反应的患者，并有望导致新的免疫方法的发展。

DESCRIPTION (provided by applicant): Approximately 3% of the world's population is infected with hepatitis C virus (HCV). Although new therapies have improved the rates of sustained response, the majority of patients fail to respond to antiviral treatment, remaining at risk for disease progression. In the current proposal, because viral clearance is likely mediated by the efficient coordination of various components of the immune response, we will explore the relative contribution of natural killer (NK) cells and dendritic cells (DCs) as well as the regulation of HCV-specific CD8+ T cell expansion and proliferation by various innate cytokines (e.g., type I IFN, IL-15). In order to elucidate the nature and kinetics of the innate and adaptive immune responses and how they might exert control over viral replication in the treatment setting, we propose three specific aims to be accomplished in cooperation with the NIDDK-sponsored Virahep-C clinical study of HCV resistance to antiviral therapy. Aim 1. To evaluate how NK cell responses contribute to the control of HCV In patients undergoing antiviral therapy. We hypothesize that patients who demonstrate relatively diminished NK cell activity at baseline will have a greater chance of resistance to antiviral therapy; moreover, we will examine how NK responses are modified by therapy. Aim 2. Determine how the frequency and function of myeloid (mDC) and plasmacytoid dendritic cells (pDC) correlate with response to antiviral therapy. Viral kinetic responses (e.g., null vs. fast response) will be correlated with frequency of DCs and level of IFN-a and IL-12 production. We will also examine in vitro and directly ex vivo the immunoregulatory cross-talk between DCs and NK cells. Aim 3. To precisely define the mechanisms underlying enhanced proliferation of HCV-specific CD8+ T cells with successful antiviral therapy. The maturation defects and functional impairment of HCV-specific CTL responses appear to be reversible with antiviral therapy, and our preliminary data suggest that innate cytokines (e.g., IL-15) may be critical. This information will enhance our understanding of the pathogenesis of this common disease, will provide biomarkers for identifying patients more likely to respond or not respond to antiviral therapy earlier in their course and, hopefully, will lead to development of novel immunotherapeutic approaches.