Inhibition of Liver Macrophage activation in SIV infected macaques

SIV 感染猕猴肝脏巨噬细胞活化的抑制

• 批准号: 8466826
• 负责人: Donald L Sodora
• 金额: $ 30.44万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466826
• 关键词: Address; Atherosclerosis; Autopsy; Beds; Blood; Blood Circulation; CD4 Positive T Lymphocytes; Caffeic Acids; Cell Count; Cell Nucleus; Cell physiology; Cells; Cellular biology; Discontinuous Capillary; Disease Outcome; Disease Progression; Escherichia coli; Evaluation; Event; Family suidae; Fibrosis; Functional disorder; Giant Cells; Gut associated lymphoid tissue; HIV; HIV Infections; Hepatocyte; Highly Active Antiretroviral Therapy; Human; Hyperplasia; Hypertrophy; Immune; Immune System Diseases; Immune response; Immune system; Immunologics; Immunology; Immunotherapeutic agent; Immunotherapy; Individual; Inflammatory; Inflammatory Response; Kupffer Cells; Label; Laboratories; Lead; Liver; Macaca; Macaca nemestrina; Macrophage Activation; Mediating; Modeling; Monkeys; Mucous Membrane; Mus; NF-kappa B; Pathogenesis; Pathology; Pathway interactions; Patients; Perfusion; Permeability; Phagocytosis; Population; Portal vein structure; Production; Protocols documentation; Receptor Signaling; Ribosomal DNA; Role; SIV; Site; TNF gene; Tail; Testing; Therapeutic; Tissues; Toll-like receptors; Viral; Viral Load result; Viral Proteins; Virus Diseases; Virus Replication; Work; caffeic acid phenethyl ester; cytokine; design; immune activation; in vivo; inhibitor/antagonist; insight; lymph nodes; macrophage; microbial; nonhuman primate; particle; prevent; public health relevance; research study; simian human immunodeficiency virus; small molecule; virus pathogenesis

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.

描述（由申请人提供）：HIV在整个身体多个组织部位引起不同的病理和免疫失调。尽管艾滋病毒本身引发了这些事件，但在艾滋病毒感染的个体中看到的长期全身免疫激活状态可能会驱动大部分观察到的免疫功能障碍。在肠道相关的淋巴组织（GALT）中，HIV介导关键免疫细胞的损失/功能障碍，导致血液中细菌产物水平升高，这有助于持续的免疫过度激活。巨噬细胞在通过Toll样受体（TLR）中检测微生物产物的关键作用及其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学中可能关键参与者。特别是，库普夫细胞是肝巨噬细胞，它将首次遇到遍及肠粘膜的任何细菌产物（通过门静脉），该提案的主要重点是研究Kupffer细胞功能障碍的潜力，从而有助于细菌产物和炎症性细胞质的升高水平。通过鉴定与增生性肥大，多核巨型细胞形成和kupffer细胞的炎症细胞因子产生相关的病毒蛋白，氨基免疫缺陷病毒（SIV） - 晶石模型已被用来提供对库普弗细胞功能的见解。在此提案中，我们将两个实验室的个人优势结合在一起，即Sodora实验室具有SIV非人类灵长类动物模型的专业知识和Crispe实验室，并具有肝脏免疫学专业知识。我们将重点放在位于肝脏正弦的库普弗细胞床上，因为这些是先天性免疫细胞观看门静脉静脉细菌产物的最早群体，并产生炎性细胞因子。我们假设全身免疫激活部分是由于肝巨噬细胞（库普弗细胞）产生炎症细胞因子的一部分。 kupffer细胞的炎症反应的治疗控制可以降低尾巴猕猴中SIV疾病进展的全身免疫激活水平。我们的第一个目的将评估在未感染的与SIV感染的尾尾猕猴的尸检时获得的肝库普弗细胞的激活状态。我们的第二个目标将通过抑制使用NF-KB抑制剂的猪尾猕猴的kupffer细胞中这种炎症反应来从机械学上评估NF-KB途径（由病毒和细菌产物刺激）的作用。 CAPE（咖啡酸苯乙基酯）可防止NF-KB转移到核中，并在多酮颗粒中注入的Cape被Kupffer细胞优先吸收。这些研究以 Crispe博士的实验室使用斗篷颗粒来评估小鼠的Kupffer细胞功能。该探索性R21旨在提供有关SIV发病机理的肝脏和库普弗细胞生物学研究所研究领域的见解。通过在SIV-猕猴模型中抑制肝巨噬细胞激活，我们将确定靶向肝巨噬细胞是否是HIV感染患者免疫疗法的潜在策略。