New Strategies to Prevent Death from Influenza

预防流感死亡的新策略

• 批准号: 7133190
• 负责人: KENDALL A SMITH
• 金额: $ 144.03万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7133190
• 关键词: cytokine; death; immunity; infection; influenza

DESCRIPTION (provided by applicant): This project, entitled "New Strategies to Prevent Death from Influenza" is designed to respond to the imminent introduction of new strains of influenza virus into the population, either through a natural pandemic or via bioterrorism. Two strategies are described; one to treat the Acute Respiratory Distress Syndrome (ARDS) by blocking immunopathology after infection, and secondly, to prevent/attenuate the ARDS by new approaches to develop "T cell vaccines and adjuvants." In the first aim, we plan to extend on our data, which already indicate that anti-TNF agents can prevent the ARDS, by determining how long after infection TNF can still be effective, by testing new short-acting truncated TNF receptors (TRUCEPT), by blocking the cells that are responsible for producing TNF and other proinflammatory cytokines via recombinant proteins that block the costimulatory T cell molecule OX40, and by activating an inhibitory molecule, CD200R, on antigen presenting cells (APC). In the second aim we plan to extend experimental data, which indicate that vaccination with live influenza viruses can markedly attenuate morbidity and mortality to a lethal exposure to a virus strain that does not share antibody cross-reacting antigens. Subsequently, we plan to compare immunity raised using live viruses with safe, non-replicating Adenovirus vaccine vectors that contain influenza genes in addition to an adjuvant gene that activates NF-kB, thereby upregulating APC function. To ensure maximal immunization of T cells, two approaches will be tested to boost the number and function of responding T cells: interleukin-2 (IL2) and OX40L-lg. Thus, the strategy is to use a dual approach to the development of safe vaccines that can be used to immunize the world's population, including those individuals most at risk, the very young, the elderly, and the immunocompromised. This is a collaborative effort between two established research teams, one in New York City, and one in London, UK with complementary skills and whose members know each other well. The experiments are focused on preclinical animal models, but are designed to build toward relevant clinical problems. If successful, this research effort will provide the foundation for the development of a universal approach to the prevention and treatment of one of the world's most dangerous microbes, one that kills hundreds of thousands yearly.

描述（由申请人提供）：该项目题为“预防流感死亡的新策略”，旨在应对新的流感病毒株即将通过自然大流行或生物恐怖主义引入人群。描述了两种策略；一是通过阻断感染后的免疫病理学来治疗急性呼吸窘迫综合征（ARDS），二是通过开发“T细胞疫苗和佐剂”的新方法来预防/减轻ARDS。第一个目标是，我们计划扩展我们的数据，通过测试新的短效截短 TNF 受体 (TRUCEPT)，确定感染后多长时间 TNF 仍然有效，这些数据已经表明抗 TNF 药物可以预防 ARDS ，通过阻断共刺激 T 细胞分子 OX40 的重组蛋白来阻断负责产生 TNF 和其他促炎细胞因子的细胞，并激活抗原呈递细胞上的抑制分子 CD200R （APC）。在第二个目标中，我们计划扩展实验数据，这些数据表明，接种活流感病毒可以显着降低致命暴露于不具有抗体交叉反应抗原的病毒株的发病率和死亡率。随后，我们计划将使用活病毒产生的免疫力与安全、非复制的腺病毒疫苗载体进行比较，这些载体除了激活 NF-kB 的佐剂基因外还含有流感基因，从而上调 APC 功能。为了确保 T 细胞的最大免疫，将测试两种方法来增强应答 T 细胞的数量和功能：白介素-2 (IL2) 和 OX40L-lg。因此，该战略是采用双重方法来开发安全疫苗，可用于对世界人口进行免疫，包括高危人群、幼儿、老年人和免疫功能低下的人群。这是两个已建立的研究团队之间的合作成果，一个位于纽约市，另一个位于英国伦敦，具有互补的技能，并且其成员彼此非常了解。这些实验主要针对临床前动物模型，但旨在解决相关的临床问题。如果成功，这项研究工作将为开发一种通用方法来预防和治疗世界上最危险的微生物之一奠定基础，这种微生物每年会导致数十万人死亡。