Metabolic Regulation of the Th2 Response

我们的免疫系统是抵御感染的主要屏障，但它也是一把双刃剑。不适当或过度的免疫反应可能和完全没有反应一样有害。Th2免疫是一种与肠道蠕虫感染相关的免疫反应。它会导致肿胀、肌肉收缩和水样粘液的产生增加，所有这些都有助于清除病原体。然而，同样的Th2反应也与过敏和哮喘有关，在这些情况下，Th2免疫的相同标志是有害的；它们甚至是致命的。例如，组织肿胀和水样粘液是花粉热的许多典型症状背后的原因，而在肺部深处，同样的过程会导致许多严重的哮喘发作。目前，我们对th2介导的疾病的最佳治疗策略是引起整个免疫系统普遍抑制的药物，如皮质类固醇。能够让我们有选择地微调Th2反应的方法将是一个重大的进步。我们在这个项目中的目标是了解Th2反应背后的细胞生物学，并确定支持或抑制Th2发育的关键途径，以便将来我们可以操纵这些途径来控制Th2免疫。我们关注的特定途径是代谢途径，控制细胞如何利用能量发挥作用的途径。最近的证据表明，免疫细胞的激活与它们能量使用的巨大变化有关，因为激活的细胞开始疯狂地燃烧糖，试图为它们的快速增殖和增强的功能提供燃料。该项目的目的是评估是否有可能利用获取特定能源作为操纵免疫细胞功能的方法。我们的假设是，参与Th2反应的细胞，比如对抗寄生虫感染的细胞，对糖的依赖程度低于参与免疫反应的细胞，比如防御病毒的细胞。我们提出，改变免疫系统的能量使用模式可以决定主导的免疫反应类型，从而决定病原体或人是茁壮成长还是死亡。我们预计，我们产生的数据和我们提供的新认识不仅将加速其他科学家寻求了解感染疾病过程的工作，而且还将使我们在生物技术和制药行业的同事受益，他们将把这些信息推进药物和治疗干预。我们的目标是，我们取得的进展将导致对Th2免疫的有针对性的干预，以及针对肠道蠕虫感染、过敏和哮喘的新疗法。我们的工作还可以支持决策者和非政府组织，他们促进采取行动，尽可能在全球卫生方面取得最大进展。

Our immune system is our principal defence against infection, but it is a double-edged sword. Inappropriate or over-exuberant immune responses can be as harmful as no response at all. Th2 immunity is a type of immune response that is associated with intestinal worm infections. It causes swelling, muscle contraction and an increase in the production of watery mucus, all of which contribute to flushing out the pathogen. However, the same Th2 response is also associated with allergies and asthma, and in these contexts the same hallmarks of Th2 immunity are damaging; they can even be fatal. Tissue swelling and watery mucus are behind many of the classic symptoms of hay fever, for example, and deeper in the lungs the same processes are responsible for many, severe asthma attacks. At the moment, our best treatment strategies for Th2-mediated diseases are drugs that cause generalised suppression of the whole immune system, like corticosteroids. Approaches that would enable us to fine-tune the Th2 response, selectively, would be a significant advance. Our aim in this project is to understand the cell biology behind the Th2 response and to identify key pathways that support or suppress Th2 development, so that in the future we can manipulate these pathways to control Th2 immunity. The particular pathways that we focus on are metabolic pathways, ones controlling how cells use energy to function. Recent evidence suggests that the activation of immune cells is associated with a dramatic change in their energy usage, as the activated cells begin to burn sugar in a frenetic attempt to fuel their rapid proliferation and increased function. The purpose of this project is to assess whether it is possible to use access to particular energy sources as a method of manipulating the function of immune cells. Our hypothesis is that the cells that participate in a Th2 response, such as one against a parasitic worm infection, are less reliant on sugar than the cells involved in an immune response that defends against a virus, for example. We propose that altering the immune system's patterns of energy use could determine the type of immune response that dominates, and hence whether the pathogen or the person will thrive or die. We anticipate that the data we produce and the new understanding we provide will not only accelerate the work of other scientists seeking to understand disease processes in infections, but will also benefit our colleagues in biotech and pharmaceutical industry who will move this information forward into drugs and therapeutic interventions. Our aim is that the progress we make will lead to targeted interventions in Th2 immunity and new therapies both for intestinal worm infections, and for allergies and asthma. Our work may also support policy makers and non-governmental organisations who promote action to achieve the best possible advancement in global health.