Adenovirus vectors and complement system

腺病毒载体和补体系统

• 批准号: 7147257
• 负责人: Andrea na Amalfitano
• 金额: $ 15.49万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-05 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7147257
• 关键词: Adenoviridae; Kupffer' s cell; complement; complement pathway regulation; enzyme linked immunosorbent assay; gene delivery system; immune response; immunocytochemistry; laboratory mouse; laboratory rat; neutrophil; platelet aggregation; transfection /expression vector; vascular endothelium

DESCRIPTION (provided by applicant): Ongoing studies make it clear that the intravenous injection of high doses of Adenovirus (Ad) based vectors offer a tremendous potential for treatment of disseminated cancers, inherited diseases, vascular diseases, as well for gene therapy of the liver for a variety of hepatic/genetic diseases. However, the systemic administration of Ad based vectors is currently viewed as a highly risky maneuver, as significant acute toxicities can be incurred, including chemokine/cytokine release, endothelial cell damage, Kupffer cell activation, hypotension, thrombocytopenia (low platelet counts), and as noted in the Gelsinger tragedy, the systemic inflammatory response syndrome and death. Precious little is known about the innate systems that are immediately triggered by injection of an Ad vector at high doses. Activation of these systems is predicted to be pivotal in initiating and/or modulating subsequent host immune responses, both innate and adaptive. One of these first line innate host defense systems is the complement system. Inappropriate complement activation can result in a number of dire consequences, including anaphylactoid reactions, ARDS (adult respiratory distress syndrome), hypotensive shock, DIC (disseminated intravascular coagulation), cytokine release and systemic inflammatory response syndromes. More specifically, complement activation products released after complement activation (i.e: C3a, C5a) are potent inflammatory mediators, which are known to activate Kupffer cells, as well activate vascular endothelium, leading to neutrophil recruitment, and platelet aggregation. Intriguingly, many of these consequences are also noted after high dose Ad injections. Based upon these considerations, we forward the following Central Hypothesis: "Ad vector interactions with the complement system results in many of the limitations and toxicities typically attributed to the use of Ad vectors". The aims of this proposal will directly test the central hypothesis. The results of this line of investigation will move the field of gene transfer using systemically administered Ad vectors forward.

描述（由申请人提供）：正在进行的研究表明，静脉注射高剂量的腺病毒（Ad）载体为治疗播散性癌症、遗传性疾病、血管疾病以及肝脏基因治疗提供了巨大的潜力用于多种肝脏/遗传疾病。然而，基于 Ad 的载体的全身给药目前被认为是一种高风险的操作，因为可能会引起显着的急性毒性，包括趋化因子/细胞因子释放、内皮细胞损伤、库普弗细胞激活、低血压、血小板减少症（血小板计数低）和正如基辛格悲剧中所指出的，全身炎症反应综合征和死亡。 对于高剂量注射 Ad 载体会立即触发的先天系统，我们知之甚少。预计这些系统的激活对于启动和/或调节随后的宿主免疫反应（先天性和适应性）至关重要。这些第一线先天宿主防御系统之一是补体系统。不适当的补体激活可导致许多可怕的后果，包括过敏样反应、ARDS（成人呼吸窘迫综合征）、低血压休克、DIC（弥散性血管内凝血）、细胞因子释放和全身炎症反应综合征。更具体地说，补体激活后释放的补体激活产物（即：C3a、C5a）是有效的炎症介质，已知它们可以激活库普弗细胞，也可以激活血管内皮，导致中性粒细胞募集和血小板聚集。有趣的是，在注射高剂量广告后也注意到了许多这些后果。 基于这些考虑，我们提出以下中心假设：“Ad载体与补体系统的相互作用导致许多通常归因于Ad载体的使用的限制和毒性”。该提案的目的将直接检验中心假设。这一系列研究的结果将推动使用系统施用的 A​​d 载体进行基因转移的领域向前发展。