Restoring Immune Function Following Radiation Injuries by TLR9 Agonist Treatment

描述（由申请人提供）：迫切需要研究人类对放射性核事件的反应，以制定有效的医疗对策。核爆炸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。尽管存在公共健康危险，但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。如果事件真的发生，幸存者的当务之急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。我们假设在辐射损伤或辐射复合损伤（RCI）后给予免疫反应调节剂（IRM）治疗可以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。我们开发了一种近交小鼠模型来表征辐射和RCI对免疫系统的影响，并测试几种IRM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，我们发现一种含有cpg的寡脱氧核苷酸（ODN）可以模拟细菌DNA，在辐射损伤或RCI后1天给予小鼠，可以发出高度保护性的免疫反应。CpG ODNs通过刺激toll样受体9 （TLR9）受体激活细胞，其生物学活性取决于其核酸序列和结构。我们发现一种特殊的CpG ODN序列，称为CpG ODN 2336，保护小鼠免受损伤后感染和败血症，即使是暴露于6 Gy全身辐射剂量的小鼠合并烧伤。该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Aim 1中，将进行药代动力学研究，以确定放射后小鼠皮下（s.c）给药CpG ODN 2336的有效剂量范围和时间。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。毒性研究也将进行。目的2研究将描述CpG ODN治疗对造血和免疫系统的生物活性和作用机制。目的3将研究和比较CpG ODN在人和小鼠免疫细胞上的激活特性的物种特异性。这些比较研究的结果将进一步推动CpG ODNs作为辐射损伤后保护性治疗的翻译潜力。目的4实验将检验CpG ODN治疗放射复合损伤（RCI）小鼠模型的有效性。RCI模型将包括烧伤或头部损伤的辐射。总的来说，这些研究的结果将为翻译CpG odn作为治疗核事件后可能发生的各种损伤的有效医学对策提供临床前数据。

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.