Therapy of acute radiation syndrome and its complications by mesenchymal stromal cells conditioned with Toll-like receptor 9 agonists

Toll样受体9激动剂诱导间充质基质细胞治疗急性放射综合征及其并发症

• 批准号: 9899920
• 负责人: JAMES A. LEDERER
• 金额: $ 58.23万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9899920
• 关键词: Acute; Agonist; Animal Model; Bacteria; Bacterial Counts; Bacterial Infections; Biological; Bone Marrow; Cell Communication; Cell Proliferation; Cell Survival; Cell Therapy; Cells; Cessation of life; Chronic; Clinical Data; Complex; Complication; Data; Development; Differentiation and Growth; Disease; Dose; Environment; Event; Exposure to; Fibroblasts; Gene Targeting; Goals; Hematopoietic; Hematopoietic System; Homeostasis; Homing; Immune; Immune System Diseases; Immune response; Immune system; In Vitro; Individual; Infection; Inflammation; Inflammatory; Injury; Knowledge; Longevity; Lung; Lung infections; Measures; Mediating; Mediator of activation protein; Mesenchymal; Mitochondria; Modeling; Monitor; Morbidity - disease rate; Mucous Membrane; Mus; Nature; Nuclear; Nuclear Accidents; Opportunistic Infections; Organ; Outcome; Oxidative Stress; Pathway interactions; Phagocytosis; Phenotype; Process; Production; Radiation; Radiation Dose Unit; Radiation Injuries; Radiation Toxicity; Radiation exposure; Radio; Recovery; Research; Resolution; Respiratory Burst; Sepsis; Stimulus; Surface; Survivors; TLR9 gene; Technology; Testing; Therapeutic; Translating; World Health; antimicrobial; base; conditioning; cytokine; experimental study; healing; immune function; immune system function; immunomodulatory therapies; improved; in vivo; infection risk; injury recovery; innovation; insight; medical countermeasure; mesenchymal stromal cell; migration; mortality; novel strategies; organ injury; pre-clinical; preconditioning; protective effect; radiation effect; radiation recovery; radiation-induced injury; response; response to injury; transcriptome; transcriptome sequencing; treatment optimization; treatment strategy

Project Summary There remains an urgent need to develop medical countermeasures to treat acute and delayed radiation injuries that could result from a large-scale, radio-nuclear event. The unpredictable nature, as well as the complexity of the injuries from a nuclear blast makes this a challenging world health problem. If an event does occur, an immediate concern for survivors will be the development of opportunistic infections as radiation and injury damage the immune system. As there are limited treatment options for protecting the potentially high numbers of individuals that might be exposed to varying radiation, new and innovative strategies are necessary to advance the treatment of radiation injury. Cellular based therapy has shown benefit in numerous disease processes associated with injury and immune dysfunction. Mesenchymal stromal cells (MSCs) are ideal candidates for a cellular therapeutic as we have shown that they improve survival in murine sepsis by modulating the immune response and promoting resolution of inflammation. Pre-conditioning of MSCs may improve their efficacy in the oxidative inflammatory microenvironment into which they are administered after radiation injury. We have shown that the Toll-like receptor 9 agonist (CpG-ODN) may be an optimal candidate for pre-conditioning of MSCs. We found that a specific CpG-ODN sequence protected mice from post-injury infection and sepsis post-radiation. Thus, the overarching aim of this proposal is to develop MSCs and CpG pre-conditioned MSCs with the long- term goal of using CpG-MSCs as a cellular therapeutic to reduce the mortality and morbidity of radiation exposure injuries. We hypothesize that pre-conditioning MSCs by CpG-ODN stimulation will enhance their beneficial effects on anti-microbial immune function and hematopoietic system recovery to improve radiation injury and recovery. To test our hypothesis, we propose three aims. In Aim 1 we will systematically test and develop MSCs and CpG-ODN pre-conditioned MSCs as a treatment for radiation-induced injury and infection in a pre-clinical animal model looking at survival, bacterial counts, and immune cell recovery. Our preliminary data show that mice given CpG conditioned MSCs had a lower mortality rate following radiation and infection compared with untreated and MSC-treated mice. In Aim 2 we will explore the biological effects of CpG-ODN stimulation on MSC phenotype, function, homing to injury, response to oxidative stress, as well as their interaction with irradiated and non-irradiated immune cells. We will also use RNAseq to profile the CpG-ODN response of MSCs and identify mechanistic targets. In Aim 3 we will use data gained during the course of this project to identify mechanisms and pathways that mediate the beneficial activity of CpG-ODN conditioned MSCs. In this aim we will also determine whether treatment with MSCs and CpG MSCs impacts development of delayed effects of radiation. This research has significance, as knowledge gained from this study will provide pre-clinical data for translating CpG pre-conditioned MSCs as effective medical countermeasures for treating the variety of injuries that could occur following a radio-nuclear event.

项目摘要 迫切需要开发医疗对策来治疗急性和延迟辐射受伤 这可能是由大规模的无线核事件造成的。不可预测的本质以及 核爆炸带来的伤害使这是一个具有挑战性的世界健康问题。如果确实发生了事件，则 对幸存者的直接关注将是机会感染作为辐射和伤害的发展 损坏免疫系统。因为有限的治疗选择可以保护潜在的高数字 在可能暴露于不同辐射的个人中，必须采取新的和创新的策略才能提高 辐射损伤的治疗。基于细胞的疗法已显示出许多疾病过程中的好处 与损伤和免疫功能障碍有关。间充质基质细胞（MSC）是A 细胞治疗，因为我们已经证明它们通过调节免疫来提高鼠败血症的生存率 反应和促进炎症的分辨率。 MSC的预处理可能会提高其在 氧化炎症微环境在放射线损伤后将其施用。我们已经显示了 Toll样受体9激动剂（CPG-ODN）可能是预先调节MSC的最佳候选者。我们 发现特定的CpG-ODN序列保护小鼠免受伤害后感染和脓毒症后辐射。 因此，该提案的总体目的是开发MSC和CPG预先条件的MSC，并具有长期 使用CPG-MSC作为细胞治疗以降低辐射暴露的死亡率和发病率的术语目标 受伤。我们假设通过CPG-ODN刺激预先调节MSC将增强其有益 对抗微生物免疫功能和造血系统恢复的影响，以改善辐射损伤和 恢复。为了检验我们的假设，我们提出了三个目标。在AIM 1中，我们将系统地测试和开发MSC 和CPG-ODN预先调节的MSC作为辐射诱导的损伤和感染的治疗 动物模型研究生存，细菌计数和免疫细胞恢复。我们的初步数据表明 辐射和感染后，给予CPG条件MSC的小鼠的死亡率较低 未处理和MSC处理的小鼠。在AIM 2中，我们将探索CpG-ODN刺激对生物学作用对 MSC表型，功能，归因于伤害，对氧化应激的反应以及它们与 辐照和非辐照的免疫细胞。我们还将使用RNASEQ介绍MSC的CPG-ODN响应 并确定机械目标。在AIM 3中，我们将使用该项目过程中获得的数据来识别 介导CPG-ODN条件MSC的有益活性的机制和途径。在这个目标中我们 还将确定使用MSC和CPG MSC处理是否会影响 辐射。这项研究具有重要意义，因为从这项研究中获得的知识将为临床前数据提供 将CPG预先调节的MSC转换为治疗伤害种类的有效医学对策 这可能发生在无线电核事件之后。