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: 10242660
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242660
• 关键词: Adult; Advisory Committees; American; Anti-Inflammatory Agents; Antibodies; Antigen-Presenting Cells; Area; Beds; Biological Assay; Blood specimen; Burn Centers; Burn injury; Cancer Patient; Caring; Cells; Cessation of life; Child; Childhood; Childhood Injury; Clinical; Clinical Trials; Critical Illness; Data; Debridement; Development; Disease; Down-Regulation; FDA approved; Flow Cytometry; Funding; Future; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; IL7 gene; Immune; Immune checkpoint inhibitor; Immunobiology; Immunohistochemistry; Immunologic Adjuvants; Immunologic Surveillance; Immunosuppression; Immunotherapy; Incubated; Infection; Inflammatory; Inflammatory Response; 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; Sampling; Scientist; Sepsis; Skin graft; Surgeon; Testing; Therapeutic; Time; Tissues; Training; Trauma; United States; Universities; Up-Regulation; Work; Wound Infection; adverse outcome; burn wound; career; clinical development; design; experimental study; graft failure; heat injury; immune checkpoint; immune function; immunomodulatory therapies; improved outcome; infection risk; inhibitor/antagonist; injured; laser capture microdissection; macrophage; mortality; mortality risk; new therapeutic target; outcome prediction; patient population; pediatric burn injury; pediatric patients; peripheral blood; phenotypic biomarker; programmed cell death protein 1; programs; receptor expression; restoration; septic; severe injury; tool; wound bed; wound healing

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.

项目总结/摘要 鉴于小儿热损伤的患病率和发病率，我们必须完全了解 并确定与这种疾病有关的所有知识缺口。小儿烧伤的免疫生物学状况不佳 如果能被理解，就能打开通向新的治疗目标的大门。我以前的研究训练，现在 研究咨询委员会，强大的指导和实践作为一个小儿烧伤外科医生将允许我 获取数据并帮助缩小这一知识差距。这项建议的总体目标是进一步发展我的 职业生涯成为外科医生，科学家，其重点是儿科热损伤的免疫生物学，目标是 使用免疫调节疗法以减少不良后果。使用在其他形式中验证的方法 我们将检验我们的中心假设，即PD-1通路的上调是 与小儿烧伤后的免疫抑制和不良结局相关;以及 通过使用PD-1途径抑制剂，这种免疫抑制是离体可逆的。热 受伤儿童将接受纵向血液采样以及组织床采样， 清创和移植手术。PD-1/PD-L1/L2的白细胞表达将通过流式细胞仪进行定量 细胞仪先天性和适应性免疫功能将通过离体刺激测定和流式细胞术来测量。 细胞仪将沿着用pro-PD-1/PD-L1/L2测定伤口床巨噬细胞表达。 使用免疫组织化学和激光捕获的炎症和抗炎表型标志物 显微切割和mRNA分析。此外，我们将确定是否免疫抑制作用的 使用离体方法，热损伤是可逆的。我们将与来自 使用PD-1通路抑制剂、GM-CSF或重组IL-7治疗热损伤儿童。细胞将被 通过离体刺激测定和流式细胞术评价免疫功能的恢复。本研究将 成为第一个评估PD-1通路在儿科热损伤中的作用的人。这是特别 考虑到免疫检查点抑制剂在其他形式疾病中的临床意义， 癌症和败血症这个职业发展奖将产生进一步的初步数据，也为我提供 与必要的工具，以成功地竞争未来的独立资金在儿科热领域， 损伤