Innate immunity to adenovirus vectors

对腺病毒载体的先天免疫

基本信息

批准号：
8242001
负责人：
Dmitry Shayakhmetov
金额：
$ 38.61万
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 2015-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8242001
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

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

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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. PUBLIC HEALTH RELEVANCE: Adenovirus vectors (Ad) are the most common viral vector type used in clinical studies worldwide. Despite extensive preclinical data on the use of Ad in gene transfer applications, Ad's use for gene therapy in humans is severely limited due to life-threatening innate immune and inflammatory responses that arise after intravascular delivery of the high (and potentially therapeutic) virus doses. This proposal is to fill the major void in our understanding of Ad-induced inflammation in vivo triggered after intravascular virus delivery. These studies will provide new insights into fundamental mechanisms of the 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）是全球临床研究中使用的最常见的病毒载体类型。血管内分娩后，广告会引起多方面的宿主先天免疫和炎症反应，从而极大地损害了由于剂量限制的全身毒性而导致的基于AD治疗的安全性和功效。控制这种全身性抗AD炎症反应的分子和细胞机制仍然很了解。通过分析在关键炎症介质中注射带囊膜变化的AD向量中的小鼠敲除敲除小鼠敲除后体内的炎症开始，我们进行了一个原始的观察，即AD与23个整联蛋白和巨噬细胞外表面受体相互作用触发IL-111介导的独特炎症途径。该途径的激活启动了依赖于功能性IL-1RI信号传导的下游细胞因子和趋化因子级联反应。但是，我们的研究还表明，除了这种细胞因子的产生外，静脉内AD给药可诱导快速促炎的MF死亡，并将促炎性白细胞涌入受影响的部位。该提案的具体目的旨在定义AD诱导的炎症的每个已知组成部分对静脉内AD给药后观察到的临床相关的全身毒性的贡献。在特定的目标1中，我们将研究与体内介导AD诱导的炎性巨噬细胞死亡有关的分子机制，及其在激活全身性抗AD炎症反应中的作用。在特定的目标2中，我们将分析炎症白细胞的表型标记和功能激活状态，静脉注射后在脾脏和肝脏中积聚，以及它们在介导急性全身性抗AD炎症反应中的作用。在特定的目标3中，我们将构建新型的AD向量，以避免与23个整合素相互作用，并分析其基因递送和体内的全身毒性谱。这些研究将提高我们对宿主防御病毒病原体的基本机制的理解，并最终可能导致开发安全有效的AD媒介，以治疗多种临近和获得的人类疾病。公共卫生相关性：腺病毒载体（AD）是全球临床研究中使用的最常见的病毒载体类型。尽管有关在基因转移应用中使用AD的广泛临床前数据，但由于威胁生命的先天免疫和炎症反应，AD在人类中对基因治疗的使用受到严重限制，这些反应是在高（且潜在治疗）病毒剂量的血管内递送后产生的。该建议是在我们对血管内病毒后触发的AD诱导的体内炎症的理解中填补主要空隙。这些研究将为宿主防御病毒病原体的基本机制提供新的见解，并最终可能导致开发安全有效的AD媒介，以治疗各种天生和获得的人类疾病。