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: 8606812
• 负责人: Donald L Sodora
• 金额: $ 23.7万
• 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 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606812
• 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在全身多个组织部位引起明显的病理和免疫失调。虽然HIV病毒本身引发了这些事件，但在HIV感染个体中观察到的系统性免疫激活的长期状态可能导致了许多观察到的免疫功能障碍。在肠道相关淋巴组织（GALT）中，HIV介导关键免疫细胞的丧失/功能障碍，导致血液中细菌产物水平增加，这有助于持续的免疫过度激活。巨噬细胞通过toll样受体（tlr）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中起关键作用。特别是，库普弗细胞是肝脏巨噬细胞，它将是第一个遇到任何穿过肠道粘膜的细菌产物（通过门静脉）的细胞，本提案的主要重点将是研究库普弗细胞功能障碍是否可能导致细菌产物和炎症细胞因子水平升高。猴免疫缺陷病毒(SIV)-猕猴模型已被用于通过鉴定与库普弗细胞增生、肥大、多核巨细胞形成和炎症细胞因子产生相关的病毒蛋白来深入了解库普弗细胞的功能。在这个提议中，我们结合了两个实验室的各自优势，Sodora实验室拥有SIV非人灵长类动物模型的专业知识，Crispe实验室拥有肝脏免疫学的专业知识。我们将重点关注位于肝窦的库普弗细胞床，因为这些是第一批先天免疫细胞看到门静脉细菌产物，并产生炎症细胞因子。我们假设全身免疫激活部分是由肝巨噬细胞（Kupffer细胞）产生炎性细胞因子引起的。治疗性控制库普弗细胞的炎症反应可以降低全身免疫激活水平和猪尾猕猴SIV疾病进展的迹象。我们的第一个目标是评估未感染SIV的猪尾猴与感染SIV的猪尾猴尸检时获得的肝库普弗细胞的激活状态。我们的第二个目标是利用NF-kB抑制剂抑制长尾猕猴库普弗细胞的炎症反应，从而从机制上评估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）阻止NF-kB向细胞核的易位，并且在聚酮颗粒中注入的CAPE优先被Kupffer细胞吸收。这些研究建立在