Regulatory T cells in control of the immune response to acute bacterial infection and sepsis

调节性 T 细胞控制对急性细菌感染和脓毒症的免疫反应

• 批准号: G0700153/1
• 负责人: Daniel Altmann
• 金额: $ 54.48万
• 依托单位: Imperial College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2007
• 资助国家: 英国
• 起止时间: 2007 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=G0700153%2F1
• 关键词: Regulatory; cells; control; immune; response

The immune system is evolved to mount a rapid, protective response against infection. At the same time, it is tightly regulated in order that this response does not overshoot so as to cause inflammatory damage. A key way in which such regulation comes about is through the action of a white blood cell population termed regulatory T cells, or Tregs. Relatively little work has previously been done on the role that Tregs might play in regulating the immune response in the context of severe bacterial infection. These infections can involve sepsis, the condition whereby there is an inflammatory response throughout the body, often leading to organ failure or, in the condition termed septic shock , rapid fall in blood pressure. Septic shock leads to death in 40-70% of cases. There is thus an urgent need to gain a better understanding of the immunological events leading to this condition and so design better medicines. A current view suggests that it might be the consequence of an exaggerated, damaging, immune response. Little work has been done on the role of Tregs in controlling this, though we have recently been doing work to find out. The patient needs to mount a rapid and effective immune response to infection, so might this involve some mechanism for taking the brakes off with respect to Treg control, yielding a bigger response? Alternatively, perhaps bacteria have evolved mechanisms to subvert the immune response, producing substances that are able to further enhance Treg function and constrain immunity. A third possibility is that a large amount of control by Tregs is indeed brought to bear, but this is an appropriate response to limit disease damage. We will address these possibilities in a well-defined transgenic mouse model of gram-positive sepsis. The work involves defining the Treg changes that occur at the site of infection and in the whole body after infecting with the gram-positive bacteria, Streptococcus pyogenes. We will then see what happens if the influence of Tregs is removed, either by giving an antibody or by doing the work in knockout mice. These studies should aid our fundamental understanding of Tregs during bacterial infection, as well as offering clues for future therapeutic manipulation of the immune response in septic shock.

免疫系统的进化是为了对感染产生快速的保护性反应。同时，它受到严格的调节，以便这种反应不会过度，从而导致炎症损伤。这种调节的一个关键途径是通过一种称为调节性T细胞（Tcl 2）的白色血细胞群的作用。相对较少的工作，以前已经做了的作用，THEOTH可能发挥调节免疫反应的背景下，严重的细菌感染。这些感染可能涉及脓毒症，即全身出现炎症反应的情况，通常导致器官衰竭，或者在称为脓毒性休克的情况下，血压迅速下降。感染性休克导致40-70%的病例死亡。因此，迫切需要更好地了解导致这种情况的免疫学事件，从而设计更好的药物。目前的观点认为，这可能是一种夸大的、破坏性的免疫反应的结果。虽然我们最近一直在做研究，但关于TdR在控制这一过程中的作用的研究很少。病人需要对感染产生快速有效的免疫反应，那么这是否涉及某种机制，可以解除Treg控制的刹车，产生更大的反应？或者，也许细菌已经进化出破坏免疫反应的机制，产生能够进一步增强Treg功能和抑制免疫的物质。第三种可能性是，Tactus确实进行了大量的控制，但这是限制疾病损害的适当反应。我们将在明确的革兰氏阳性脓毒症转基因小鼠模型中解决这些可能性。这项工作涉及定义感染部位和感染革兰氏阳性细菌化脓性链球菌后全身发生的Treg变化。然后，我们将看到，如果通过给予抗体或在基因敲除小鼠中进行这项工作，消除了TdR的影响，会发生什么。这些研究有助于我们对细菌感染过程中THBE的基本理解，并为未来脓毒性休克免疫反应的治疗操作提供线索。