Targeting cytotoxic immunity for the resolution of neuropathic pain

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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.