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.

项目概要 仍然迫切需要制定治疗急性和迟发性辐射损伤的医疗对策 这可能是大规模射电核事件造成的。不可预测的性质以及复杂性 核爆炸造成的伤害使其成为一个具有挑战性的世界健康问题。如果某个事件确实发生，则会出现 幸存者最关心的问题是辐射和损伤等机会性感染的发生 损害免疫系统。由于保护潜在大量患者的治疗选择有限 对于可能暴露于不同辐射的个人，需要采取新的创新策略来推进 放射损伤的治疗。基于细胞的疗法已在许多疾病过程中显示出益处 与损伤和免疫功能障碍有关。间充质基质细胞 (MSC) 是理想的候选者 细胞疗法，我们已经证明它们通过调节免疫来提高小鼠脓毒症的存活率 反应并促进炎症消退。 MSCs 的预处理可能会提高其功效 放射损伤后给药的氧化炎症微环境。我们已经展示了 Toll 样受体 9 激动剂 (CpG-ODN) 可能是预处理 MSC 的最佳候选者。我们 发现特定的 CpG-ODN 序列可以保护小鼠免受损伤后感染和辐射后败血症。 因此，该提案的总体目标是开发具有长期作用的 MSC 和 CpG 预处理 MSC。 使用 CpG-MSC 作为细胞治疗剂来降低辐射暴露的死亡率和发病率的长期目标 受伤。我们假设通过 CpG-ODN 刺激预处理 MSC 将增强其有益效果 对抗菌免疫功能和造血系统恢复的影响，改善放射损伤和 恢复。为了检验我们的假设，我们提出了三个目标。在目标 1 中，我们将系统地测试和开发 MSC 和 CpG-ODN 预条件化 MSC 作为临床前放射损伤和感染的治疗方法 动物模型着眼于生存、细菌计数和免疫细胞恢复。我们的初步数据表明 与接受 CpG 条件的 MSC 治疗的小鼠相比，接受辐射和感染的小鼠死亡率较低 未经治疗和 MSC 治疗的小鼠。在目标 2 中，我们将探讨 CpG-ODN 刺激对 MSC 表型、功能、损伤归巢、氧化应激反应及其与 受辐射和未受辐射的免疫细胞。我们还将使用 RNAseq 来分析 MSC 的 CpG-ODN 反应 并确定机械目标。在目标 3 中，我们将使用在该项目过程中获得的数据来识别 介导 CpG-ODN 条件 MSC 有益活性的机制和途径。为了这个目标我们 还将确定 MSC 和 CpG MSC 治疗是否会影响延迟效应的发展 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以下疾病提供临床前数据： 将 CpG 预处理的 MSC 转化为治疗各种损伤的有效医疗对策 这可能发生在无线电核事件之后。