Innate immunity to adenovirus vectors

对腺病毒载体的先天免疫

基本信息

批准号：
8444584
负责人：
Dmitry Shayakhmetov
金额：
$ 36.29万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-07-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8444584
关键词：
Acute Adenovirus Vector Affect Anti-Inflammatory Agents Anti-inflammatory Apoptosis Regulator Biological Process Capsid Caspase-1 Cell Death Cell Surface Receptors Cells Cessation of life Clinical Clinical Research Collaborations Cytokine Activation Data Development Dose Dose-Limiting Event Exposure to Funding Gene Delivery Gene Transfer Goals Host Defense Mechanism Human Immune Immune response Individual Inflammation Inflammation Mediators Inflammatory Inflammatory Response Injection of therapeutic agent Institutes Integrins Interleukin-1 Interleukin-11 Intravenous Knock-out Knockout Mice Lead Leukocytes Life Liver Mediating Molecular Mouse Strains Natural Immunity Outcome Pathway interactions Physiological Process Production Publishing Role Safety Signal Pathway Signal Transduction Site Spleen Systems Biology Therapeutic Tissues Toxic effect Transgenic Mice Universities Viral Viral Vector Virus Washington base cell type chemokine clinically relevant cytokine defined contribution design design and construction gene therapy human disease improved in vivo insight macrophage novel pathogen pre-clinical public health relevance receptor response vector

项目摘要

DESCRIPTION (provided by applicant): Adenovirus vectors (Ad) are the most common viral vector type used in clinical studies worldwide. Upon intravascular delivery, Ad elicits multifaceted host innate immune and inflammatory responses that drastically compromise both the safety and the efficacy of the Ad-based therapy due to a dose-limiting systemic toxicity. The molecular and cellular mechanisms governing this systemic anti-Ad inflammatory response remain poorly understood. By analyzing the initiation of inflammation in vivo after the injection of capsid-modified Ad vectors into mice knockout for critical inflammatory mediators, we have made an original observation that Ad interaction with 23 integrins and macrophage cell-surface receptors triggers a unique inflammatory pathway mediated by IL-11. Activation of this pathway initiates a downstream cytokine and chemokine cascade that depends on functional IL-1RI signaling. However, our studies also indicate that, in addition to this cytokine production, intravenous Ad administration induces a rapid pro-inflammatory MF death and the influx of pro-inflammatory leukocytes into affected sites. The Specific Aims of this proposal are designed to define the contribution of each of the known components of Ad-induced inflammation into the clinically relevant systemic toxicity observed after the intravenous Ad administration. In Specific Aim 1, we will investigate the molecular mechanisms involved in mediating Ad-induced pro- inflammatory macrophage cell death in vivo, and its role in activating systemic anti-Ad inflammatory response. In Specific Aim 2, we will analyze the phenotypic markers and functional activation states of inflammatory leukocytes, accumulating in the spleen and liver after intravenous Ad injection, and their role in mediating the acute systemic anti-Ad inflammatory response. In Specific Aim 3, we will construct novel Ad vectors that would avoid interaction with 23 integrins and analyze their gene delivery and systemic toxicity profiles in vivo. These studies will improve our understanding of the fundamental mechanisms of host defense against viral pathogens and may ultimately lead to the development of safe and effective Ad vectors for the therapy of a wide range of inborn and acquired human diseases.

描述（由申请人提供）：腺病毒载体（Ad）是全世界临床研究中最常用的病毒载体类型。血管内递送后，Ad 会引发多方面的宿主先天免疫和炎症反应，由于剂量限制性全身毒性，从而极大地损害了基于 Ad 的治疗的安全性和有效性。控制这种全身性抗 Ad 炎症反应的分子和细胞机制仍然知之甚少。通过分析将衣壳修饰的 Ad 载体注射到关键炎症介质敲除小鼠体内后体内炎症的启动，我们得出了一个原始观察结果：Ad 与 23 个整合素和巨噬细胞表面受体的相互作用触发了一种独特的炎症途径，该途径由IL-11。该通路的激活会启动依赖于功能性 IL-1RI 信号传导的下游细胞因子和趋化因子级联。然而，我们的研究还表明，除了产生这种细胞因子外，静脉注射 Ad 还会诱导促炎性 MF 快速死亡以及促炎性白细胞流入受影响部位。该提案的具体目标旨在定义 Ad 诱导炎症的每种已知成分对静脉注射 Ad 给药后观察到的临床相关全身毒性的贡献。在具体目标1中，我们将研究介导Ad诱导体内促炎性巨噬细胞死亡的分子机制，及其在激活全身抗Ad炎症反应中的作用。在具体目标2中，我们将分析静脉注射Ad后在脾脏和肝脏中积累的炎症白细胞的表型标志物和功能激活状态，以及它们在介导急性全身抗Ad炎症反应中的作用。在具体目标 3 中，我们将构建新型 Ad 载体，避免与 23 个整合素相互作用，并分析它们的基因传递和体内系统毒性特征。这些研究将提高我们对宿主防御病毒病原体基本机制的理解，并可能最终开发出安全有效的Ad载体，用于治疗各种先天性和后天性人类疾病。