Cellular mechanism of immune dysfunction following burn injury

烧伤后免疫功能障碍的细胞机制

• 批准号: 8445370
• 负责人: Bruce A Cairns
• 金额: $ 28.7万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-06 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8445370
• 关键词: Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Binding; Burn injury; CD8B1 gene; Cause of Death; Cell Death; Cells; Dendritic Cells; Effectiveness; Exhibits; Family; Family member; Health; Human; Immune; Immune System Diseases; Immune Tolerance; Immune response; Immune system; Immunologics; Immunotherapeutic agent; Impairment; Infection; Inflammatory; Injury; Mediating; Mediator of activation protein; Molecular; Multiple Organ Failure; Mus; Nucleotides; Organ failure; Patients; Pattern; Phase; Predisposition; Process; Production; Pseudomonas aeruginosa; Receptor Signaling; Relative (related person); Rest; Role; Secondary to; Sepsis; Signal Pathway; Signal Transduction; Skin graft; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Toll-like receptors; Up-Regulation; allograft rejection; clinically relevant; cytokine; design; immune function; in vivo; macrophage; microbial; novel therapeutics; prevent; receptor; receptor expression; research study; response; skin allograft; wound

DESCRIPTION (provided by applicant): The leading causes of death following serious burn injury are sepsis and multiple system organ failure secondary to profound innate and adaptive immune dysfunction, though the controlling mechanism for the response is unknown. Major determinants of immune activity are the innate Toll-like receptor (TLR) and nucleotide binding oligomerization domain (NOD)-like receptor (NLR) families. These are expressed by many immune cells and their primary function is to sense microbial molecules leading to cytokine release or cell death. Our overall hypothesis is that impairment of both the innate and adaptive immune systems after burn injury is mediated directly by TLR and NLR signaling. The proposed experiments are designed to test this hypothesis during both immunopathogenic phases after burn injury and investigate innate receptor-blockade as a possible immunotherapeutic approach for clinically relevant issues facing burn patients. First, to determine the mechanism by which TLR and NLR signaling controls the innate immune system after injury: We will determine phenotypic and functional (cytokine and cell death) changes of MF and DC using an animal model of burn injury. We will correlate TLR and NLR expression with changes in their function during early and late after burn injury. We will then use TLR and NLR deficient mice to validate that the altered burn injury-mediated innate immune response is mediated through innate-receptor signaling. Second, to determine the mechanism by which innate signaling controls the adaptive immune response after burn injury: We will examine the effect of burn injury on the expression and activation of TLR and NLR on CD4+ and CD8+ T cells and relevant T cell subsets. We will correlate changes in TLR and NLR expression with the ability of T cells to elicit an adaptive immune response. To determine the relative importance of both direct (expression of innate receptors on T cells) and indirect (expression on MF or DC) innate receptor expression in mediating the adaptive response to burn injury, we will transfer T cells or MF and DC, deficient in innate signaling receptors, into burn or sham recipients and test T cell immune function and survival. Third, to demonstrate that innate receptors are critical for the dysfunctional immunologic response to burn injury in vivo: We will use mice deficient in TLR and NLR innate signaling to examine the role of innate receptors in mediating skin allograft rejection and preventing establishment of effective immune tolerance after burn. We will examine the importance of innate signaling pathways in mediating Pseudomonas aeruginosa susceptibility early and late after burn injury using mice deficient in TLR and NLR signaling.

描述（由申请人提供）：严重烧伤后死亡的主要原因是败血症和继发于深刻先天和适应性免疫功能障碍的多个系统器官失败，尽管该反应的控制机制尚不清楚。免疫活性的主要决定因素是先天性收费受体（TLR）和核苷酸结合寡聚结构域（NOD）类似受体（NLR）家族。这些由许多免疫细胞表达，它们的主要功能是感知导致细胞因子释放或细胞死亡的微生物分子。我们的总体假设是，烧伤损伤后的先天和适应性免疫系统受损直接由TLR和NLR信号传导介导。该提出的实验旨在在烧伤后的两个免疫病变阶段测试这一假设，并研究先天受体阻滞，是针对烧伤患者面临的临床相关问题的一种免疫治疗方法。首先，为了确定TLR和NLR信号在受伤后控制先天免疫系统的机制：我们将使用烧伤损伤的动物模型来确定MF和DC的表型和功能（细胞因子和细胞死亡）变化。我们将将TLR和NLR表达与烧伤后的早期和晚期的功能变化相关联。然后，我们将使用TLR和NLR缺乏小鼠来验证改变烧伤损伤介导的先天免疫反应是通过先天受体信号传导介导的。其次，为了确定先天信号在烧伤后控制适应性免疫反应的机制：我们将检查烧伤损伤对TLR和NLR对CD4+和CD8+ T细胞的表达和激活以及相关T细胞亚群的影响。我们将将TLR和NLR表达的变化与T细胞引起适应性免疫反应的能力相关联。为了确定直接（先天受体在T细胞上的表达）和间接（在MF或DC上的表达）先天受体表达在介导对烧伤损伤的适应性反应中的间接（表达），我们将转移T细胞或MF和DC，缺乏先天信号受体，将其转移到燃烧或模拟T细胞免疫功能和生存中。第三，为了证明先天受体对于体内烧伤损伤的功能障碍的免疫反应至关重要：我们将使用缺乏TLR和NLR先天信号的小鼠来检查先天受体在介导皮肤同种异体移植抑制和防止燃烧后有效免疫耐受性的作用。我们将研究先天信号通路在使用TLR和NLR信号不足的小鼠烧伤后的早期和晚期中介导铜绿假单胞菌易感性的重要性。

项目成果

Mammalian target of rapamycin regulates a hyperresponsive state in pulmonary neutrophils late after burn injury.

• DOI: 10.1002/jlb.3ab0616-251rrr
• 发表时间: 2018-05
• 期刊: Journal of leukocyte biology
• 影响因子: 5.5
• 作者: Dunn JLM;Kartchner LB;Gast K;Sessions M;Hunter RA;Thurlow L;Richardson A;Schoenfisch M;Cairns BA;Maile R
• 通讯作者: Maile R