Background. We and others have identified signs of immune dysregulation in patients with psychosis relative to community-based controls. Interleukin (IL)-6 stands out as the most consistently raised cytokine in the liquor and blood of patients, including evidence in drug-naïve patients. Although adjunctive anti-inflammatory treatments in psychosis are promising, these have yielded mixed results. This is likely to reflect a failure to correctly classify or select patients with immune dysfunction. A current hypothesis is that only a subset, but not all, patients with psychosis present with an altered immune-inflammatory state that could benefit from adjunctive anti-inflammatory treatments. Deep immuno-phenotyping and cell-based functional assays of peripheral blood immune cells combined with conventional cytokine assays can be used as a tool to correctly classify patients according to an immune-inflammatory state. This innovative approach will provide significant insights into disease immuno-pathogenesis and targets for personalised treatments. Aims. a) To conduct deep immuno-phenotyping and cell-based functional assays of peripheral blood immune cells from psychosis patients and matching controls; b) To investigate associations between blood immune cells and symptom dimensions (positive, negative, depressive, and cognitive symptoms) at baseline and after inhibition of IL-6 pathway with tocilizumab (IL-6 inhibitor). Methods. This proposal is part of the ongoing Psychosis Immune Mechanism Stratified Medicine Study (PIMS). The sample will comprise immune-active psychosis patients (n=50), non-immune active patients (n=25), and healthy controls (n=25) recruited from Birmingham and Cambridge/UK. Signs of immune dysfunction in patients will be informed by PIMS mendelian randomisation and machine learning algorithms. Baseline blood samples and clinical data will be available for all the participants. For the immune-active patients, biological and clinical measures will be taken at baseline and post-tocilizumab infusion on days 7, 14, and 28. A number of cutting-edge methods will be employed for a comprehensive characterisation of innate and adaptive immune cells using multi-colour panels for flow cytometry. Cell surface expression of IL-6R and related proteins (e.g., gp130) will be quantified on defined immune cell subsets, and the responsiveness of these cells to IL-6 signalling using a pSTAT3 phosflow assay. In addition, the impact of tocilizumab in trial patients will be assessed by administration of exogenous IL-6 stimulation using phosflow assay. Research Merit: PIMS study stands out for being rigorously designed to identify immune-active psychosis patients and for conducting a trial precisely focused on subgroups with immune dysregulation Our proposal will employ innovative methods to advance the immunopsychiatry research field, with the potential to introduce novel diagnostic tools and more effective and personalised treatments in psychiatry. More information: https://gtr.ukri.org/projects?ref=MR%2FS037675%2F1.
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