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

基本信息

  • 批准号:
    8242153
  • 负责人:
  • 金额:
    $ 19.44万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2012
  • 资助国家:
    美国
  • 起止时间:
    2012-01-01 至 2013-11-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): 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 contact with LPS-stimulated fibrocytes incites a Th1 cytokine response from naive 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. PUBLIC HEALTH RELEVANCE: Sepsis is a complex systemic inflammatory response to infection that can produce serious consequences. It promotes several immune defects that result in a high mortality rate. Our studies indicate that bone marrow-derived fibrocytes have immune functions, including phagocytosis, pro-inflammatory cytokine production, and the ability to activate naive T cells, that could be beneficial in cases of sepsis. The purpose of this proposal is to find the mechanisms behind the advantageous effects of fibrocytes in order to exploit them as a treatment for sepsis.
描述(由申请人提供):骨髓源性纤维细胞是独特的成纤维细胞样细胞,具有类似于成体干细胞/祖细胞的多种功能和可塑性。它们潜在的免疫功能和实用属性促使我们对纤维细胞在脓毒症中的作用进行了初步研究。我们的初步数据表明,一种创新的细胞疗法,过继转移纤维细胞,保存T细胞数量,并显着提高败血症的生存。最初的研究还表明,与LPS刺激的纤维细胞接触,激发了来自幼稚T细胞的Th 1细胞因子应答,并且来自脓毒症腹部的纤维细胞增加了CD 4 + T细胞的增殖。因此,我们假设:纤维细胞的治疗性给药通过增加具有Th 1表型的T细胞的增殖来改善脓毒症的结果。使用小鼠盲肠结扎穿孔(CLP)模型,特异性目的I试图确定T细胞亚型在纤维细胞增强脓毒症存活机制中的作用。为了比较生存参数,血浆IL-6水平将用作CLP诱导死亡率的预测生物标志物。通过在诱导脓毒症后的不同时间间隔进行过继转移,将确认疗效窗口和与生存期相关的参数。特异性目的II将确定负责纤维细胞相关的T细胞增殖和活化增加的基本机制。将鉴定负责T细胞和纤维细胞之间相互作用的共刺激分子。此外,将确定纤维细胞产生细胞因子的影响,并验证感兴趣的特定细胞因子的作用。最后,机制研究的结果将用于检查细菌产物对纤维细胞编程与T细胞有益相互作用的影响。虽然这些研究被设计为具有独立价值,但它们也将为进一步研究这种独特的细胞类型在脓毒症的免疫病理学中提供重要的背景。 公共卫生相关性:脓毒症是一种复杂的全身性感染炎症反应,可产生严重后果。它促进了导致高死亡率的几种免疫缺陷。我们的研究表明,骨髓来源的纤维细胞具有免疫功能,包括吞噬作用、促炎细胞因子产生和激活幼稚T细胞的能力,这在脓毒症的情况下可能是有益的。该提案的目的是找到纤维细胞的有利作用背后的机制,以便利用它们作为脓毒症的治疗。

项目成果

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JEAN A NEMZEK其他文献

JEAN A NEMZEK的其他文献

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{{ truncateString('JEAN A NEMZEK', 18)}}的其他基金

Direct mechanisms of fibrocyte immunotherapy in sepsis
脓毒症纤维细胞免疫治疗的直接机制
  • 批准号:
    8962221
  • 财政年份:
    2015
  • 资助金额:
    $ 19.44万
  • 项目类别:
Direct mechanisms of fibrocyte immunotherapy in sepsis
脓毒症纤维细胞免疫治疗的直接机制
  • 批准号:
    9108409
  • 财政年份:
    2015
  • 资助金额:
    $ 19.44万
  • 项目类别:
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
  • 财政年份:
    2012
  • 资助金额:
    $ 19.44万
  • 项目类别:
Proj 2: Lung injury
项目 2:肺损伤
  • 批准号:
    6891183
  • 财政年份:
    2005
  • 资助金额:
    $ 19.44万
  • 项目类别:
Role of Cytokines in Two Hit Organ Injury
细胞因子在两次击中器官损伤中的作用
  • 批准号:
    6466248
  • 财政年份:
    2002
  • 资助金额:
    $ 19.44万
  • 项目类别:
Role of Cytokines in Two Hit Organ Injury
细胞因子在两次击中器官损伤中的作用
  • 批准号:
    6623486
  • 财政年份:
    2002
  • 资助金额:
    $ 19.44万
  • 项目类别:
Role of Cytokines in Two Hit Organ Injury
细胞因子在两次击中器官损伤中的作用
  • 批准号:
    7068642
  • 财政年份:
    2002
  • 资助金额:
    $ 19.44万
  • 项目类别:
Role of Cytokines in Two Hit Organ Injury
细胞因子在两次击中器官损伤中的作用
  • 批准号:
    6896855
  • 财政年份:
    2002
  • 资助金额:
    $ 19.44万
  • 项目类别:
Role of Cytokines in Two Hit Organ Injury
细胞因子在两次击中器官损伤中的作用
  • 批准号:
    6749034
  • 财政年份:
    2002
  • 资助金额:
    $ 19.44万
  • 项目类别:
Proj 2: Lung injury
项目 2:肺损伤
  • 批准号:
    7551281
  • 财政年份:
  • 资助金额:
    $ 19.44万
  • 项目类别:

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