Role of Macrophage Costimulatory Molecules in Polymicrobial Sepsis

巨噬细胞共刺激分子在多种微生物脓毒症中的作用

• 批准号: 7211817
• 负责人: JEFFREY A. GOLD
• 金额: $ 38.44万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-15 至 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7211817
• 关键词: Anti-Inflammatory Agents; Anti-inflammatory; Binding; Biological; Biological Markers; CD14 gene; CD28 gene; CD40 Antigens; CD80 gene; CTLA4 gene; Cells; Cellular Immunity; Class; DNA Binding; Data; Disease; Disease Marker; Gold; Human; Immune; Immune response; Immunity; In Vitro; Individual; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-6; Investigation; Kinetics; Knockout Mice; Ligands; Ligation; Macrophage Activation; Mediating; Modeling; Molecular Profiling; Mononuclear; Mus; NF-kappa B; Natural Immunity; Outcome; Pathway interactions; Patients; Phase; Plasma; Play; Production; Protein Isoforms; Puncture procedure; Regulation; Reporting; Research Personnel; Role; Sepsis; Septic Shock; Severities; Survivors; System; T-Lymphocyte; TLR4 gene; TNFRSF5 gene; TNFSF5 gene; Testing; Up-Regulation; attenuation; chemokine; cytokine; improved; in vivo; intercellular cell adhesion molecule; macrophage; monocyte; mortality; neutrophil; novel; pathogen; programs; receptor; septic

DESCRIPTION (provided by applicant): Inflammation in sepsis is controlled primarily by the degree of macrophage activation. Costimulatory molecules are a class of receptors capable of macrophage activation in adaptive immunity. Ligation of macrophage expressed CD40, CD80/CD86 and ICAM by CD154, CD28/CTLA4 and LFA-1 on activated T- cells, increases NF-kB DNA binding and the ratio of stimulatory/inhibitory isoforms of C/EBPb. This results in increased production of numerous inflammatory cytokines. However, the role for costimulatory molecules in the innate immune response during polymicrobial sepsis is not well described. We recently described CD40- /- mice have delayed mortality with polymicrobial sepsis with attenuations in NF-kB activity and the ratio of stimulatory/inhibitory C/EBPb. We now present data that neutrophils, a main component of innate immune response in sepsis, can directly activate macrophages via engagement of the costimulatory molecules CD40, CD80/CD86 and ICAM in vitro. In vivo, CD80/CD86-/- mice have improved survival compared to WT mice after CLP. This was associated with a reduction in NF-kB, the ratio of stimulatory/inhibitory C/EBPb and levels of IL-6 and IL-10 in BAL and plasma. Similar to what has been reported in moels of adaptive immunity, inhibtion for multiple costimulatory molecules provided additional benefit. Both CD40/CD80/CD86-/- mice and ICAM neutralization in CD80/CD86-/- mice improved survival compared to CD80/86-/- mice after CLP. In humans with sepsis, we found upregulation of PMN expressed CD28, CTLA4 and CD154, and monocyte expressed CD40, CD80/CD86 and ICAM compared to healthy controls. In addition, the soluble isoforms of CD154, CD28, ICAM and CTLA4 were upregulated in septic patients compared to healthy controls. Furthermore, levels of sCD28 and sCD154 were only upregulated in non-survivors, suggesting a potential role as a biomarker of disease activity. Together, these results suggest an important role for costimulatory molecules in sepsis. In this proposal we plan to extend these observations to: 1. Characterize the kinetics and activity of the CD40-CD154, CD80/CD86-CD28/CTLA4 and ICAM-LFA-1 systems in a murine model of polymicrobial sepsis, 2. Test the effect of inhibition of multiple costimulatory molecules in sepsis via a novel CD40/CD80/CD86-/- mouse, and 3. To fully assess the significance of costimulatory molecule expression and activity both in vivo and ex vivo in humans with sepsis and septic shock

描述（由申请人提供）：脓毒症中的炎症主要由巨噬细胞活化程度控制。共刺激分子是一类在获得性免疫中能够激活巨噬细胞的受体。通过活化的T细胞上的CD 154、CD 28/CTLA 4和LFA-1连接表达CD 40、CD 80/CD 86和ICAM的巨噬细胞，增加NF-κ B DNA结合和C/EBPb的刺激/抑制同种型的比率。这导致许多炎性细胞因子的产生增加。然而，共刺激分子在多微生物脓毒症的先天性免疫反应中的作用还没有得到很好的描述。我们最近描述了CD 40- /-小鼠在多微生物脓毒症中具有延迟的死亡率，其中NF-kB活性和刺激性/抑制性C/EBPb的比率减弱。我们现在提供的数据表明，中性粒细胞，在脓毒症中的先天性免疫反应的主要组成部分，可以直接激活巨噬细胞通过参与的共刺激分子CD 40，CD 80/CD 86和ICAM在体外。在体内，CLP后，与WT小鼠相比，CD 80/CD 86-/-小鼠的存活率有所改善。这与BAL和血浆中NF-kB、刺激性/抑制性C/EBPb比值以及IL-6和IL-10水平的降低相关。类似于在获得性免疫的分子中所报道的，对多种共刺激分子的抑制提供了额外的益处。CLP后，与CD 80/86-/-小鼠相比，CD 40/CD 80/CD 86-/-小鼠和CD 80/CD 86-/-小鼠中的ICAM中和均改善了存活率。在脓毒症患者中，我们发现与健康对照相比，PMN表达CD 28、CTLA 4和CD 154，单核细胞表达CD 40、CD 80/CD 86和ICAM。此外，与健康对照相比，脓毒症患者中可溶性同种型CD 154、CD 28、ICAM和CTLA 4上调。此外，sCD 28和sCD 154的水平仅在非幸存者中上调，表明其作为疾病活动的生物标志物的潜在作用。总之，这些结果表明，共刺激分子在脓毒症中的重要作用。在本提案中，我们计划将这些观察扩展到：1。在多微生物败血症的鼠模型中表征CD 40-CD 154、CD 80/CD 86-CD 28/CTLA 4和ICAM-LFA-1系统的动力学和活性，2.通过新的CD 40/CD 80/CD 86-/-小鼠测试多种共刺激分子的抑制在脓毒症中的作用，和3.全面评估体内和体外共刺激分子表达和活性在脓毒症和脓毒性休克患者中的意义