Mechanisms for Fibrocyte Mediated Enhancement of Survival in Sepsis

纤维细胞介导的脓毒症生存增强机制

• 批准号: 8403669
• 负责人: JEAN A NEMZEK
• 金额: $ 22.21万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-01-01 至 2014-01-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8403669
• 关键词: Abdomen; Adoptive Transfer; Adult; Apoptosis; Biological Markers; Bone Marrow; CD4 Positive T Lymphocytes; Cell Communication; Cell Count; Cell Therapy; Cells; Complex; Data; Defect; Disease; Environment; Fibroblasts; Hour; Immune; In Vitro; Infection; Inflammatory; Inflammatory Response; Interleukin-6; Investigation; Knowledge; Ligation; Link; Mediating; Mediator of activation protein; Modeling; Mus; Outcome; Phagocytosis; Phenotype; Plasma; Population; Positioning Attribute; Process; Production; Puncture procedure; Regulation; Research Design; Role; Sepsis; Spleen; Stem cells; Surface; Survival Rate; T-Cell Proliferation; T-Lymphocyte; Therapeutic; Work; arm; cell type; cytokine; immune function; immunopathology; improved; innovation; insight; interest; lymph nodes; microbial; mortality; paracrine; programs; response; septic; stem

Project Summary Bone-marrow derived fibrocytes are unique, fibroblast-like cells with diverse functions and plasticity akin to adult stem/progenitor cells. Their potential immune functions and practical attributes prompted our preliminary investigations of the previously unexplored role of fibrocytes in sepsis. Our preliminary data suggest that an innovative cell therapy, adoptive transfer of fibrocytes, conserves T cell numbers and significantly improves survival in sepsis. Initial studies also show that contct with LPS-stimulated fibrocytes incites a Th1 cytokine response from na¿ve T cells and that fibrocytes derived from the septic abdomen increase the proliferation of CD4+ T cells. Therefore, we hypothesize: Therapeutic administration of fibrocytes improves outcome in sepsis by increasing the proliferation of T cells with the Th1 phenotype. Using the murine cecal ligation and puncture (CLP) model, Specific Aim I seeks to determine the role of T cell subtypes in the mechanisms behind fibrocyte enhanced sepsis survival. To compare survival parameters, plasma IL-6 levels will be used as a predictive biomarker of CLP-induced mortality. By performing adoptive transfer at various intervals after the induction of sepsis, the window of efficacy and parameters associated with survival will be confirmed. Specific Aim II will determine the basic mechanisms responsible for the fibrocyte-associated increases in T cell proliferation and activation. The co-stimulatory molecules responsible for interactions between T cells and fibrocytes will be identified. In addition, the impact of cytokine production by fibrocytes will be determined and the role of specific cytokines of interest will be validated. Finally, the findings from mechanistic studies will be used to examine the effects of bacterial products on the programming of fibrocytes for beneficial interactions with T cells. While these studies are designed to be of independent value, they will also supply important background for further investigation of this unique cell type in the immunopathology of sepsis.

项目摘要 骨髓源性纤维细胞是一种独特的成纤维细胞样细胞，具有多种功能和可塑性， 成人干/祖细胞。它们潜在的免疫功能和实用属性促使我们进行了初步的研究。 纤维细胞在脓毒症中以前未探索的作用的研究。我们的初步数据表明， 创新的细胞疗法，纤维细胞的过继转移，保存T细胞数量并显著改善 脓毒症中的生存。最初的研究还表明，与LPS刺激的纤维细胞接触会刺激Th 1细胞因子 来自幼稚T细胞的反应和来自脓毒症腹部的纤维细胞增加了 CD 4 + T淋巴细胞。因此，我们假设：纤维细胞的治疗性给药改善了 通过增加具有Th 1表型的T细胞的增殖来治疗脓毒症。使用小鼠盲肠结扎 和穿刺（CLP）模型，具体目标I旨在确定T细胞亚型在机制中的作用， 纤维细胞增强脓毒症存活率。为了比较存活参数，将使用血浆IL-6水平作为 CLP诱导死亡率的预测生物标志物。通过在移植后的不同时间间隔进行过继转移， 将确认诱导脓毒症、疗效窗口和与存活相关的参数。具体 目的II将确定纤维细胞相关的T细胞增殖的基本机制， 增殖和活化。负责T细胞和T细胞之间相互作用的共刺激分子， 将鉴定纤维细胞。此外，将确定纤维细胞产生细胞因子的影响， 将验证感兴趣的特异性细胞因子的作用。最后，机械研究的结果将是 用于检查细菌产物对纤维细胞编程的影响，以实现有益的相互作用 T细胞。虽然这些研究旨在具有独立价值，但它们也将提供重要的 进一步研究脓毒症免疫病理学中这种独特细胞类型的背景。