Restoring Immune Function Following Radiation Injuries by TLR9 Agonist Treatment

通过 TLR9 激动剂治疗恢复放射损伤后的免疫功能

• 批准号: 8573161
• 负责人: JAMES A. LEDERER
• 金额: $ 58.43万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-09 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8573161
• 关键词: Address; Aftercare; Agonist; Award; Bacterial DNA; Base Sequence; Biological; Biological Assay; Blast Cell; Blood Cells; Burn injury; Cells; Clinical Data; Closed head injuries; Comparative Study; Complex; Craniocerebral Trauma; Cytokine Activation; DNA; Detection; Development; Dose; Drug Kinetics; Effectiveness; Equilibrium; Event; Female; Flow Cytometry; Hematopoietic System; Hematopoietic stem cells; Homeostasis; Human; Image; Immune; Immune response; Immune system; Immunity; Immunoassay; Immunology; In Vitro; Individual; Infection; Injury; Laboratories; Measures; Mediating; Medical; Modeling; Mus; National Institute of Allergy and Infectious Disease; Natural regeneration; Nature; Nuclear; Nucleic acid sequencing; Opportunistic Infections; Patients; Phase Transition; Population; Production; Property; Public Health; Radiation; Radiation Injuries; Recovery; Research; Sepsis; Signal Transduction; Species Specificity; Structure; Survivors; System; TLR9 gene; Testing; Time; Tissues; Toxic effect; Translating; Trauma; Treatment Effectiveness; Whole-Body Irradiation; World Health; absorption; antimicrobial; chemokine; design; effective therapy; immune function; in vivo; injured; male; mouse model; pre-clinical; public health relevance; radiation effect; receptor; research study; response; subcutaneous; treatment effect; uptake

DESCRIPTION (provided by applicant): Research addressing the human response to radionuclear events is urgently needed for developing effective medical countermeasures. The unpredictable nature as well as the complexity of the injuries from a nuclear blast makes this a challenging world health problem. Despite the public health danger, there are limited treatment options for protecting the potentially high numbers of individuals that might be exposed to varying radiation or radiation with combined trauma. If an event does occur, an immediate concern for survivors will be the development of opportunistic infections because radiation and injury damage the immune system making it difficult for patients to resist infections. We hypothesize that giving immune response modifier (IRM) treatment after radiation injury or radiation combined injury (RCI) will protect injured individuals from the complications of these complex injuries by restoring immune system homeostasis. We developed an outbred mouse model to characterize the effects of radiation and RCI on the immune system and to test several IRM strategies as treatments for restoring immune system function after radiation and RCI. During the course of this project, we discovered that a CpG-containing oligodeoxynucleotide (ODN) that mimics bacterial DNA could signal a highly protective immune response in mice when given at 1 day after radiation injury or RCI. CpG ODNs activate cells by stimulating Toll-like receptor 9 (TLR9) receptors and their biological activities depend on their nucleic acid sequence and structure. We found that a specific CpG ODN sequence, called CpG ODN 2336, protected mice from post-injury infection and sepsis even in mice exposed to 6 Gy whole-body radiation doses with combined burn injury. This project will use this discovery to test and advance the potential of using CpG ODNs as broad protective medical countermeasures for radiation and radiation combined injury. In Aim 1, pharmacokinetic studies will be performed to determine effective dose ranges and timing for subcutaneous (s.c.) delivery of CpG ODN 2336 to mice post radiation. This aim will use a systems immunology approach to measure immune cell regeneration and anti-microbial immunity to judge effective treatment doses. Toxicity studies will also be performed. Aim 2 studies will delineate the biological activities and mechanisms-of-action for CpG ODN treatment effects on the hematopoietic and immune system. Aim 3 will investigate and compare species specificities of CpG ODN activation properties on human and mouse immune cells. The translational potential of CpG ODNs as protective treatments after radiation injury will be advanced by the results of these comparative studies. Aim 4 experiments will test the effectiveness of CpG ODN treatments in radiation combined injury (RCI) mouse models. The RCI models will include radiation with burn injury or head injury. Collectively, the results of these studies will provide pre-clinical data for translating CpG ODNs as effective medical countermeasures for treating to the variety of injuries that could occur following a nuclear event.

描述（由申请人提供）：迫切需要研究人类对辐射事件的反应，以制定有效的医疗对策。核爆炸造成的伤害的不可预测性和复杂性使其成为一个具有挑战性的世界卫生问题。尽管存在公共卫生危险，但用于保护可能暴露于不同辐射或辐射合并创伤的潜在大量个体的治疗选择有限。如果事件确实发生，幸存者的直接关注将是机会性感染的发展，因为辐射和损伤会损害免疫系统，使患者难以抵抗感染。我们假设，在放射损伤或放射复合损伤（RCI）后给予免疫应答调节剂（Immune response modifier，RRI）治疗，将通过恢复免疫系统稳态来保护受伤个体免受这些复杂损伤的并发症。我们开发了一种远系杂交小鼠模型，以表征辐射和RCI对免疫系统的影响，并测试几种免疫策略作为辐射和RCI后恢复免疫系统功能的治疗方法。在这个项目的过程中，我们发现，含有CpG的寡脱氧核苷酸（ODN），模拟细菌DNA可以信号高度保护性免疫反应，在小鼠辐射损伤或RCI后1天。CpG ODN通过刺激Toll样受体9（TLR9）来激活细胞，并且其生物活性取决于其核酸序列和结构。我们发现，一个特定的CpG ODN序列，称为CpG ODN 2336，保护小鼠免受损伤后感染和脓毒症，即使在小鼠暴露于6戈伊全身辐射剂量与复合烧伤。本项目将利用这一发现来测试和推进使用CpG ODNs作为辐射和辐射复合损伤的广泛保护性医疗对策的潜力。在目标1中，将进行药代动力学研究以确定皮下（s.c.）CpG ODN 2336在辐射后递送至小鼠。 该目标将使用系统免疫学方法来测量免疫细胞再生和抗微生物免疫，以判断有效的治疗剂量。还将进行毒性研究。目的2研究CpG ODN对造血和免疫系统的生物学活性和作用机制。目的3将研究并比较CpG ODN对人和小鼠免疫细胞激活特性的物种特异性。这些比较研究的结果将促进CpG ODNs作为辐射损伤后保护性治疗的翻译潜力。目的研究CpG ODN对放射复合伤小鼠的治疗作用。RCI模型将包括辐射与烧伤或头部损伤。总的来说，这些研究的结果将提供临床前数据，用于将CpG ODN转化为有效的医疗对策，用于治疗核事件后可能发生的各种损伤。