Targeting Cytotoxic Immunity for the Resolution of Neuropathic Pain

Neuropathic pain is caused by damage or disease of the nervous system and is by definition chronic and particularly difficult to treat. Neuropathic pain affects as many as 5 million people in the UK alone, significantly impacting quality of life as well as economic output. While many people will recover from nerve injury given time, not everyone will recover pain-free. The most challenging aspect clinically, is to get people with neuropathic pain into a recovery phase while avoiding the side-effects of the most powerful painkillers. The key question scientifically is therefore not why nerve injury is painful, but why it doesn’t resolve in certain people. Long thought of as a sensitiser of peripheral nerves, there is now an appreciation that the immune response to nerve injury may also play a role in pain resolution. Using experimental models, our lab has pioneered work into a type of killer immune cell that appears to target injured nerves for removal, thus helping to accelerate recovery to a pain-free state. Our goal is to harness this type of immune response to intervene therapeutically when the natural resolution process fails. To realise the therapeutic potential of an immune-based approach to neuropathic pain, it is crucial to translate our findings to people with painful nerve injury, and to do so in a way that targets only the components of immune system necessary for neuropathic pain resolution, thus avoiding unwanted side-effects. We have identified a suite of immune receptors with the potential to engage with sensory axons after nerve injury in the mouse. Furthermore, our preliminary data indicate that some of these receptors have homologues that are present on immune cells identified within human injured nerve tissue. We will use our novel human neuro-immune cell culture platform to confirm the functional interaction between injured sensory nerves and immune receptors. We will then perform proof-of-principal experiments targeting the most promising receptor-ligand interaction using clinically relevant therapeutic biologics. Finally, we will explore immune receptor regulation on peripheral blood cells as a biomarker of painful nerve injury in both mouse and human nerve injury. In the near term, a possible impact of this work could be future trials exploring whether novel immune therapeutics currently being used to treat cancer could be repurposed to treat neuropathic pain. This would potentially bring benefit to patients on a much shorter time scale than usual drug development pipelines. In the long-term, the novel transcriptomic and cytometric datasets generated in relation to the neuro-immune interactions of nerve injury will help us to understand the mechanisms behind the failure of immune-mediated natural resolution of neuropathic pain, paving the way to future immune discovery and personalised therapeutic intervention.