CD80 and CD86 mediated innate immune response in sepsis

CD80 和 CD86 介导脓毒症的先天免疫反应

• 批准号: 7812079
• 负责人: Anna Nolan
• 金额: $ 15.91万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7812079
• 关键词: Antibodies; Biological Assay; Biological Models; Blocking Antibodies; CD28 gene; CD80 gene; Cause of Death; Chimera organism; Clinical; Clinical Data; Clinical Trials; Coculture Techniques; Confocal Microscopy; Critical Illness; Disease; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Fostering; Goals; Grant; Human; IRAK3 gene; Immune response; Immunoblotting; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Inflammatory Response; Interleukin-6; Investigation; Laboratories; Ligands; Ligation; Macrophage Activation; Master of Science; Mediating; Mentorship; Mission; Modeling; Mus; NF-kappa B; National Heart, Lung, and Blood Institute; Nature; Pathway interactions; Patients; Production; Puncture procedure; Regulation; Role; Sepsis; Severity of illness; Signal Transduction; Small Interfering RNA; System; TRAF6 gene; Time; Training; Work; career; cytokine; experience; human IRAK1 protein; human subject; improved; in vitro Model; in vivo; macrophage; monocyte; mortality; neutrophil; pre-clinical; research study; response; septic; therapy design; transcription factor

DESCRIPTION (provided by applicant): Sepsis (systemic inflammatory response to infection) has an incidence of 750,000 cases and is the leading cause of death in critically ill patients. Treatment of sepsis has been limited and remains largely supportive in nature. Improved understanding of the mechanisms underlying inflammation in sepsis and preclinical investigation of interventions designed to reduce mortality are part of the NHLBI mission. Preliminary studies show that the costimulatory molecules, CD80 and CD86 are important in the innate immune response to sepsis. CD80/86-/- mice have improved survival, reduced inflammatory cytokine production and less NF-kappaB activation after polymicrobial sepsis produced by cecal ligation and puncture (CLP). An in vitro model using neutrophil (PMN)/macrophage co-culture leads to macrophage activation by a CD80/86 dependent pathway. During clinical investigation of sepsis we observed that PMN from septic humans have increased expression of a CD28 (a CD80/86 ligand) and mortality correlated with soluble CD28 levels. We hypothesize that macrophage expressed CD80/86 are involved in the innate immune response to sepsis. To determine the specific importance of CD80 and CD86 we will use mice congenitally deficient in these molecules as well as siRNA and inhibitory antibodies to modulate CD80 and CD86 expression in macrophages. We will investigate the expression of the CD80/86 system in human sepsis by flow cytometry and confocal microscopy and compare regulation in humans and mouse to validate the CLP model. We will then assay the effect of PMNs from normal and septic human subjects on macrophages in vitro and assess the role CD80 and CD86 using using siRNA and blocking antibodies in co-culture experiments. This is a proposal for investigation in sepsis and training which includes a completion of a Masters of Science in Clinical Investigation.The course work and the experience in the laboratory under the mentorship of Dr. Weiden are essential for developing my abilities in identifying pathophysiologic mechanisms in model systems. This grant will foster a career focused on understanding the mechanisms underlying inflammation in sepsis with the goal of developing intervensions that reduce mortality in this important disease.

描述（由申请人提供）：败血症（对感染的全身性炎症反应）的发生率为750,000例，是重症患者的死亡原因。败血症的治疗受到限制，并且在很大程度上仍然具有支持性。 NHLBI任务的一部分是败血症和旨在降低死亡率的干预措施的临床前研究的机制的了解。初步研究表明，共刺激分子CD80和CD86在对败血症的先天免疫反应中很重要。 CD80/86 - / - 小鼠的生存率提高，炎症细胞因子的产生降低，以及通过盲肠结扎和穿刺（CLP）产生的多肌醇败血症后的NF-kappab激活较少。使用中性粒细胞（PMN）/巨噬细胞共培养的体外模型导致CD80/86依赖途径的巨噬细胞激活。在对败血症的临床研究中，我们观察到化粪池的PMN具有CD28（CD80/86配体）的表达增加，并且死亡率与可溶性CD28水平相关。我们假设巨噬细胞表达的CD80/86参与了对败血症的先天免疫反应。为了确定CD80和CD86的特定重要性，我们将使用这些分子中的小鼠以及siRNA和抑制性抗体在巨噬细胞中调节CD80和CD86的表达。我们将通过流式细胞仪和共聚焦显微镜研究CD80/86系统在人类败血症中的表达，并比较人类和小鼠中的调节以验证CLP模型。然后，我们将分析正常人和化粪池受试者对体外巨噬细胞的PMN的影响，并评估使用使用siRNA并在共培养实验中阻止抗体的CD80和CD86的作用。这是一项败血症和培训调查的建议，其中包括完成临床研究的科学硕士学位。在魏登博士的指导下，在实验室的课程工作和实验室的经验对于发展我在识别模型系统中病理生理机制方面的能力至关重要。该赠款将促进专注于理解败血症炎症的机制的职业，其目的是开发降低这种重要疾病死亡率的干预措施。