Effects of Memory T Cells on the Response to Cecal Ligation and Puncture

记忆 T 细胞对盲肠结扎和穿刺反应的影响

基本信息

项目摘要

Sepsis is life-threatening organ dysfunction caused by a dysregulated host response to infection. The immune system plays a central role in this dysregulated host response; immune abnormalities have been identified in clinical sepsis and in murine cecal ligation and puncture (CLP), the most widely-used animal model of sepsis. However, the effect of a significant aspect of the immune response, the memory T cell response, has escaped investigation in the CLP model. Recent studies have demonstrated that laboratory mice lack a well-developed repertoire of memory T cells, a deficiency not present in mice “in the wild” – or in patients with sepsis. Thus, the contribution of this vital component of adaptive immunity is unknown. This gap in our understanding of the role of memory T cell populations in CLP assumes even greater importance considering reports that immune responses to sub-lethal infections in laboratory mice and “wild” mice differed substantially. Therefore, we undertook preliminary studies to determine if lack of this memory T cell component substantially effects responses to CLP. To induce a robust memory T cell repertoire, we treated C57Bl6 mice with an activating antibody to CD3ε, activating a diverse repertoire of T cells and inducing both CD4 and CD8 T cell memory while decreasing naïve T cell proportions without altering total T cell numbers. These “immune educated” mice (following a 35 day rest) respond quite differently to CLP when challenged, with an increased numbers of IFNɣ- producing CD4 T cells and a decreased numbers of TNFα producing CD8 T cells. Other changes seen in educated mice included increased neutrophil infiltration into the liver and enhancement of monocyte function. Importantly, CLP in educated mice was also associated with altered liver function, bacterial clearance, and weight loss. These findings lead to our global hypothesis: immune education alters the effects of CLP on organ function, innate immunity and outcomes. We will test this hypothesis via through comparison of immune educated mice treated with the anti-CD3ε antibody to naïve mice following CLP. We will initially identify variation in physiologic presentation and parameters of organ dysfunction and clinical outcomes along with differences in the immune response to CLP in both the innate and adaptive immune response. Once we have identified specific variations, we will determine causative T cell populations through specific T cell knockouts along with adoptive transfer experiments of memory and naïve T cells. Furthermore, we will collect peripheral blood samples from septic patients and healthy control patients and examine memory T cell populations and innate immune cell function in sepsis. Ultimately, these experiments will demonstrate the role of memory T cells in CLP and the septic immune response. Moreover, determination of this role may offer potential novel therapies for sepsis and perhaps other severe infectious or inflammatory disorders.
败血症是由宿主对感染的反应失调引起的危及生命的器官功能障碍。免疫 系统在这种失调的宿主反应中起着核心作用;免疫异常已经在 临床脓毒症和最广泛使用的脓毒症动物模型--鼠盲肠结扎穿孔(CLP)。 然而,免疫反应的一个重要方面--记忆T细胞反应--的作用却没有发挥出来 在CLP模型中进行研究。最近的研究表明,实验室小鼠缺乏发育良好的 记忆T细胞库,一个缺陷不存在于小鼠“在野生”-或败血症患者。因此 这种重要的适应性免疫成分的贡献是未知的。我们对这个角色的理解 CLP中记忆性T细胞群的数量更重要,因为有报道称, 实验室小鼠和“野生”小鼠对亚致死感染的反应有很大不同。所以我们 进行了初步研究,以确定缺乏这种记忆T细胞成分是否会显著影响 对CLP的回应为了诱导强大的记忆T细胞库,我们用活化的 CD 3 ε抗体,激活多种T细胞库,诱导CD 4和CD 8 T细胞记忆, 降低幼稚T细胞比例而不改变总T细胞数量。这些“免疫教育”的老鼠 (休息35天后)在攻击时对CLP的反应完全不同,IFN γ- 产生CD 4 T细胞和产生TNFα的CD 8 T细胞数量减少。受教育程度的其他变化 小鼠包括增加的中性粒细胞浸润到肝脏和单核细胞功能的增强。 重要的是,在受过教育的小鼠中,CLP也与肝功能、细菌清除和体重的改变有关。 损失这些发现导致了我们的全球假设:免疫教育改变了CLP对 器官功能、先天免疫和结果。我们将通过比较来验证这一假设, CLP后用抗CD 3 ε抗体处理的免疫训练小鼠与未处理小鼠相比。我们将初步确定 生理表现和器官功能障碍参数沿着临床结局的变化, 先天性和适应性免疫应答中对CLP的免疫应答的差异。一旦我们 我们将通过特异性T细胞敲除来确定致病性T细胞群, 沿着记忆和幼稚T细胞的过继转移实验。此外,我们将收集外围设备 从脓毒症患者和健康对照患者的血液样品,并检查记忆T细胞群, 脓毒症中的先天免疫细胞功能。最终,这些实验将证明记忆T细胞的作用, 和脓毒症免疫反应中的作用此外,确定这种作用可能会提供潜在的新疗法 用于败血症和其他严重的感染性或炎症性疾病。

项目成果

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Matthew David Taylor其他文献

Matthew David Taylor的其他文献

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{{ truncateString('Matthew David Taylor', 18)}}的其他基金

Effects of Memory T Cells on the Response to Cecal Ligation and Puncture
记忆 T 细胞对盲肠结扎和穿刺反应的影响
  • 批准号:
    10396029
  • 财政年份:
    2019
  • 资助金额:
    $ 19.55万
  • 项目类别:

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