Inhibition of Liver Macrophage activation in SIV infected macaques

描述(由申请人提供)：艾滋病毒在全身多个组织部位引起明显的病理和免疫失调。虽然艾滋病毒本身引发了这些事件，但在艾滋病毒感染者身上看到的系统免疫激活的长期状态可能是导致所观察到的免疫功能障碍的主要原因。在肠道相关淋巴组织(GALT)内，HIV介导关键免疫细胞的丢失/功能障碍，导致血液中细菌产物水平增加，从而导致持续的免疫过度激活。巨噬细胞通过Toll样受体(TLRs)检测微生物产物的关键作用以及它们产生参与免疫反应激活的细胞因子的能力使这些细胞可能在这种免疫病理中发挥关键作用。特别是，Kupffer细胞是肝巨噬细胞，它将首先遇到任何穿过肠道黏膜的细菌产物(通过门静脉)，这项提议的主要重点将是研究Kupffer细胞功能障碍可能导致细菌产物和炎性细胞因子水平升高。猴免疫缺陷病毒(SIV)-猕猴模型已被用于通过鉴定与Kupffer细胞增殖肥大、多核巨细胞形成和炎性细胞因子产生相关的病毒蛋白来深入了解Kupffer细胞的功能。在这项建议中，我们结合了两个实验室的各自优势，Sodora实验室具有SIV非人类灵长类模型的专业知识，Crispe实验室具有肝脏免疫学的专业知识。我们将重点关注位于肝窦的Kupffer细胞床，因为这些细胞是第一批看到门静脉细菌产物并产生炎性细胞因子的天然免疫细胞。我们假设系统免疫激活的部分原因是肝巨噬细胞(库普弗细胞)产生炎性细胞因子。对库普弗细胞炎症反应的治疗控制可以降低系统免疫激活水平和小尾猴SIV疾病进展的迹象。我们的第一个目标是评估在尸检中从未感染与SIV感染的猪尾猕猴身上获得的肝脏枯否细胞的激活状态。我们的第二个目标是通过使用一种核因子-kB抑制剂抑制猪尾猕猴Kupffer细胞中的这种炎症反应，从机械上评估核因子-kB途径(由病毒和细菌产物刺激)的作用。CAPE(咖啡酸苯乙酯)阻止了核因子-kB的移位，而注入聚酮颗粒中的CAPE优先被Kupffer细胞摄取。这些研究建立在 克里斯佩博士的实验室利用CAPE-聚酮醛颗粒评估小鼠的库普弗细胞功能。这一探索性的R21旨在为关于SIV发病机制的肝脏和Kupffer细胞生物学研究不足的领域提供见解。通过在SIV-猕猴模型中抑制肝巨噬细胞的激活，我们将确定靶向肝巨噬细胞是否为HIV感染患者免疫治疗的潜在策略。

DESCRIPTION (provided by applicant): HIV causes distinct pathology and immunologic dysregulation at multiple tissue sites throughout the body. While HIV virus itself initiates these events the prolonged state of systemic immune activation seen in HIV- infected individuals likely drives much of the observed immune dysfunction. Within gut associated lymphoid tissue (GALT), HIV mediates the loss/dysfunction of key immune cells leading to increased levels of bacterial products in the blood, which contribute to the sustained immune hyper-activation. The key role of macrophages for detecting microbial products via toll-like receptors (TLRs) and their ability to produce cytokines involved in activation of immune responses make these cells likely key players in this immune pathology. In particular, Kupffer cells are liver macrophages that will be the first to encounter any bacterial products that traverse the gut mucosa (via the portal vein), and the major focus of this proposal will be to investigate the potential for Kupffer cell dysfunction to contribute to the elevated levels of bacterial products and inflammatory cytokines. The simian immunodeficiency virus (SIV)-macaque model has been utilized to provide insights into Kupffer cell function through the identification of viral proteins associated with hyperplasia hypertrophy, multinuclear giant cell formation and inflammatory cytokine production of Kupffer cells. In this proposal we combine the individual strengths of two laboratories, the Sodora laboratory with expertise in SIV non-human primate models and the Crispe laboratory with expertise in liver immunology. We will focus on the Kupffer cell bed located in the sinusoids of the liver, as these are the first population of innate immune cells to see portal vein bacterial products, and produce inflammatory cytokines. We hypothesize that systemic immune activation results in part from the production of inflammatory cytokines by liver macrophages (Kupffer cells). And that therapeutic control of the inflammatory response of Kupffer cells can reduce the level of systemic immune activation and signs of SIV disease progression in pigtail macaques. Our first aim will assess the activation state of liver Kupffer cells obtained at necropsy from uninfected versus SIV infected pigtail macaques. Our second aim will mechanistically assess the role of the NF-kB pathway (stimulated by viral and bacterial products) by suppressing this inflammatory response in Kupffer cells of pigtail macaques utilizing an NF-kB inhibitor. CAPE (Caffeic Acid Phenethylester) prevents the translocation of NF-kB to the nucleus and CAPE infused in polyketal particles are preferentially taken up by Kupffer cells. These studies build on work by Dr. Crispe's laboratory utilizing CAPE-polyketal particles to assess Kupffer cell function of mice. This exploratory R21 is designed to provide insights into the understudied field of liver and Kupffer cell biology with regard to SIV pathogenesis. Through an inhibition of liver macrophage activation in the SIV- macaque model, we will determine if targeting liver macrophages is a potential strategy for immunotherapy in HIV-infected patients.