Targeting cytotoxic immunity for the resolution of neuropathic pain

痛苦对于保护我们免受伤害是必不可少的。然而，当疼痛变得慢性或持续时，它可能会对生活质量产生严重和有害的影响。由于休班天数和生产率下降，慢性疼痛也对经济产生重大影响。在英国，三分之一的成年人会在一生中遭受慢性疼痛，通常是由于意外或涉及神经损伤的伤害造成的。单是背部疼痛的费用就被认为每年要花费英国经济100亿英镑。神经损伤是痛苦的，这并不奇怪，但并不是每个神经损伤的人都会恢复得没有疼痛。例如，超过四分之一的患者接受手术松解被困的神经不会有明显的改善。了解原因对于开发解决神经损伤和疼痛的靶向治疗至关重要。我们知道血液中的免疫细胞对损伤做出反应，导致炎症和疼痛。然而，抗炎治疗很少能有效减轻神经损伤后的疼痛。有时会使用阿片类药物，但通常这些药物没有帮助，可能会使人上瘾，导致令人不安的副作用。人们迫切需要新的疗法。新的证据表明，免疫系统实际上可以帮助消除疼痛和炎症。我的研究表明，血液中通常与癌症抗争的免疫细胞，即所谓的自然杀伤细胞，能够移除受损的神经纤维，帮助防止持续的疼痛。然而，要使免疫疗法有效，重要的是要了解这些杀手细胞针对的特定分子，就像现在癌症治疗所实现的那样。为了开发一种针对疼痛的定向免疫疗法，该项目将揭示引导杀手对神经损伤做出免疫反应的信号。这一目标将分四个阶段实现：1)通过发现受损神经纤维显示的‘压力’信号，我们可以看到杀伤细胞如何识别他们的目标。这将通过使用干细胞技术从两只小鼠以及人类的细胞中完成。2)我将使用最先进的免疫细胞分析来跟踪和追踪小鼠神经损伤后的杀手免疫反应。这将告诉我们免疫治疗必须在何时何地进行。3)使用高清晰度和延时成像，我将观察免疫细胞和感觉神经细胞之间的物理和化学相互作用，同样来自小鼠和人类。4)最后，我将测试高度靶向的免疫治疗药物在缓解小鼠神经病理性疼痛方面的有效性。第二，该奖学金的长期目标是在神经损伤后可能出现慢性疼痛的患者的免疫系统中识别细胞特异性信号或生物标记物。这将通过比较小鼠和人类患者从神经损伤中恢复时的“杀手”免疫反应来实现。这些来自小鼠和人类血细胞的信息将为神经损伤后导致有效缓解疼痛的免疫反应提供线索。通过识别杀伤细胞是如何针对神经损伤的，我们可以利用免疫系统的力量帮助患者从痛苦的神经损伤中恢复。免疫治疗技术正在走向成熟。这项研究中提出的目标发现将使他们能够发展成为针对神经损伤相关疼痛的量身定做和高度特异的治疗方法。这将为实验室中确定的药物提供迅速进入临床试验的机会。

Pain is essential to protect us from harm. However, when pain becomes chronic or unrelenting it can have a severe and detrimental effect on quality of life. Chronic pain also has a significant impact on the economy as a consequence of days off work and reduced productivity. 1 in 3 adults in the UK will suffer from chronic pain in their lifetime, often from the result of accident or injury involving damage to a nerve. The cost of back pain alone is thought to cost the UK economy £10 billion annually.It should not come as a surprise that damage to a nerve is painful, yet not everyone with a nerve injury will go on to recover pain-free. For example, over a quarter of patients undergoing surgery to relieve a trapped nerve will not show significant improvement. Understanding why is crucial to developing targeted therapies for resolving nerve injury and pain.We know that immune cells in our blood respond to injury, causing inflammation and pain. However, anti-inflammatory treatments are rarely good at reducing pain after nerve injury. Opioid-based medicines are sometimes used, but often these are not helpful and can be addictive, causing troubling side effects. Novel therapies are desperately needed. New evidence suggests that the immune system can in fact help to resolve pain and inflammation.My work has shown that immune cells in the blood that normally fight cancer, called 'Natural Killer' cells, are capable of removing damaged nerve fibres and help to prevent ongoing pain. However, for immune-therapies to be effective, it is important to understand the specific molecules targeted by these killer cells, as is now being achieved with cancer treatment.In order to develop a targeted immune therapy for pain this project will uncover the signals guiding the killer immune response to nerve injury. This objective will be achieved in four stages:1) By discovering the 'stress' signals displayed by damaged nerve fibres, we can see how killer cells identify their target. This will be done is cells from both mice, and as well as humans by using stem cell technology.2) I will use state of the art immune cell analysis to track and trace the killer immune response in mice after nerve injury. This will tell us when and where the immune therapy must be targeted. 3) Using high definition and time-lapse imaging I will look at the physical and chemical interactions between immune cells and sensory nerve cells, again from both mice and humans.4) Finally, I will test the effectiveness of highly targeted immune therapeutic drugs on the relief of neuropathic pain in mice.A second, longer-term objective of this fellowship is to identify cell-specific signatures, or 'biomarkers', in the immune system of patients who may be at risk of developing chronic pain after nerve injury. This will be achieved by comparing the 'killer' immune response of mice and human patients as they recover from nerve injury. This information from blood cells in mice and humans will provide clues to the kind of immune response that leads to effective resolution of pain after nerve injury.By identifying how killer cells are targeted to nerve injury, we can then harness the power of the immune system to help patients recover from painful nerve injury. Immune therapeutic technologies now coming of age. The target discovery proposed in this fellowship will enable their development into tailored, and highly specific treatments for nerve-injury related pain. This will provide the opportunity for drugs identified in the laboratory to be rapidly taken forward into clinical trials.