Systemic and Local Immune Function after Pediatric Thermal Injury

小儿热损伤后的全身和局部免疫功能

• 批准号: 9768513
• 负责人: Rajan Thakkar
• 金额: $ 18.85万
• 依托单位: RESEARCH INST NATIONWIDE CHILDREN'S HOSP
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9768513
• 关键词: Adult; Advisory Committees; American; Anti-inflammatory; Antibodies; Antigen-Presenting Cells; Area; Beds; Biological Assay; Blood specimen; Burn Centers; Burn injury; Cancer Patient; Caring; Cells; Cessation of life; Child; Childhood; Clinical; Clinical Trials; Critical Illness; Data; Debridement; Development; Disease; Down-Regulation; FDA approved; Flow Cytometry; Funding; Future; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; Immune; Immune checkpoint inhibitor; Immunobiology; Immunohistochemistry; Immunologic Adjuvants; Immunologic Surveillance; Immunosuppression; Immunotherapy; Incubated; Infection; Inflammatory; Inflammatory Response; Injury; Interleukin-7; K-Series Research Career Programs; Knowledge; Laboratories; Leukocytes; Ligands; Link; Lymphocyte; Malignant Neoplasms; Measures; Mentors; Mentorship; Messenger RNA; Methods; Morbidity - disease rate; Nosocomial Infections; Ohio; Organ Transplantation; Outcome; Pathway interactions; Pediatric Hospitals; Phenotype; Population; Prevalence; Recombinants; Recording of previous events; Reporting; Research; Research Institute; Research Personnel; Research Training; Risk; Role; SLEB2 gene; Sampling; Scientist; Sepsis; Skin graft; Surgeon; Testing; Therapeutic; Time; Tissues; Training; Trauma; United States; Universities; Up-Regulation; Work; Wound Healing; Wound Infection; adverse outcome; career; clinical development; design; experimental study; graft failure; heat injury; immune checkpoint; immune function; immunoregulation; improved outcome; infection risk; inhibitor/antagonist; injured; injured children; laser capture microdissection; macrophage; mortality; mortality risk; new therapeutic target; outcome prediction; patient population; pediatric burn injury; pediatric patients; peripheral blood; phenotypic biomarker; programs; receptor expression; restoration; septic; tool; wound

PROJECT SUMMARY/ABSTRACT Given the prevalence and morbidity of pediatric thermal injury it is imperative that we completely understand and define all knowledge gaps related to this disease. The immunobiology of pediatric burn injury is not well defined and if understood can unlock the doors to novel therapeutic targets. My prior research training, current research advisory committee, strong mentorship and practice as a pediatric burn surgeon will allow me to obtain data and help close this knowledge gap. The overall objective of this proposal is to further develop my career into a surgeon-scientist whose focus is on the immunobiology of pediatric thermal injury with goals of using immunomodulation therapy to decrease adverse outcomes. Using methods validated in other forms of pediatric critical illness we will test our central hypothesis that upregulation of the PD-1 pathway is associated with immune suppression and adverse outcomes following pediatric burn injury; and that this immune suppression is reversible ex vivo through the use of PD-1 pathway inhibitors. Thermally injured children will undergo longitudinal blood sampling as well as tissue bed sampling at the time of debridement and grafting procedures. Leukocyte expression of PD-1/PD-L1/L2 will be quantified by flow cytometry. Innate and adaptive immune function will be measured by ex vivo stimulation assays and flow cytometry. Wound bed macrophage expression of PD-1/PD-L1/L2 will be measured along with pro- inflammatory and anti-inflammatory phenotypic markers using immunohistochemistry and laser capture microdissection with mRNA profiling. Furthermore, we will determine if the immune suppressive effects of thermal injury are reversible using ex vivo methods. We will co-incubate peripheral blood leukocytes from thermally injured children with inhibitors of the PD-1 pathway, GM-CSF or recombinant IL-7. Cells will then be evaluated for restoration of immune function via ex vivo stimulation assays and flow cytometry. This study will be the first to evaluate the role of the PD-1 pathway with respect to pediatric thermal injury. This is of particular importance given the clinical implications of immune checkpoint inhibitors in other forms of disease such as cancer and sepsis. This career development award will generate further preliminary data and also provide me with the tools necessary to successfully compete for future independent funding in areas of pediatric thermal injury.

项目概要/摘要 鉴于儿童热损伤的普遍性和发病率，我们有必要完全了解 并定义与该疾病相关的所有知识差距。小儿烧伤的免疫生物学尚不完善 定义并理解的话可以打开新治疗靶点的大门。我之前的研究培训，目前 研究咨询委员会、作为儿科烧伤外科医生的强有力的指导和实践将使我能够 获取数据并帮助缩小这一知识差距。该提案的总体目标是进一步发展我的 成为一名外科医生科学家，其重点是小儿热损伤的免疫生物学，其目标是 使用免疫调节疗法来减少不良后果。使用以其他形式验证的方法 儿科危重疾病 我们将检验我们的中心假设，即 PD-1 通路的上调是 与儿童烧伤后的免疫抑制和不良后果有关；还有那个 通过使用 PD-1 通路抑制剂，这种免疫抑制在体外是可逆的。热地 受伤儿童将在救治时接受纵向血液采样以及组织床采样 清创和移植程序。 PD-1/PD-L1/L2的白细胞表达将通过流式定量 细胞计数术。先天性和适应性免疫功能将通过离体刺激测定和流动来测量 细胞计数术。 PD-1/PD-L1/L2 的创面床巨噬细胞表达将与 pro-一起测量。 使用免疫组织化学和激光捕获的炎症和抗炎表型标记 具有 mRNA 分析的显微切割。此外，我们将确定是否有免疫抑制作用 使用离体方法，热损伤是可逆的。我们将共同孵育外周血白细胞 使用 PD-1 通路抑制剂、GM-CSF 或重组 IL-7 的热损伤儿童。然后细胞将 通过离体刺激测定和流式细胞术评估免疫功能的恢复。这项研究将 成为第一个评估 PD-1 通路在儿科热损伤中的作用的人。这是有特殊意义的 考虑到免疫检查点抑制剂在其他形式的疾病中的临床意义，例如 癌症和败血症。该职业发展奖将产生进一步的初步数据，并为我提供 拥有成功竞争儿科热学领域未来独立资金所需的工具 受伤。