Validation of the 18 kiloDalton Translocator Protein (TSPO) as a Novel Neuroimmunodulatory Target

The 18 kiloDalton Translocator Protein (TSPO) is a mitochondrial protein highly expressed in myeloid cells. While the full range of its functions are unknown, preclinical and in vitro studies provide suggestive evidence that TSPO ligands alter TSPO protein function to bias monocytes/macrophages and microglia towards reparative phenotypes. XBD173 and etifoxine are two TSPO ligands and represent two distinct chemotypes. Etifoxine is a benzoxaine, licenced in France (although not the UK) for the treatment of anxiety. XBD173 (Emapunil) is a phenylpurine that has recently been investigated for the treatment of anxiety, but is not licensed. The aim of this experimental medicine study is to test the hypothesis in humans that functional changes effected by TSPO can induce pro-inflammatory monocytes/macrophages and microglia to adopt a reparative phenotype. People with multiple sclerosis (MS) will be enrolled in this study because monocytes from MS patients have a chronic pro-inflammatory phenotype. Healthy volunteers (HVs) will also be enrolled to determine whether TSPO mediated effects are immune state dependant. The primary objective of this study is to determine the effects of TSPO ligand binding on monocyte/macrophage phenotype in humans. The secondary objectives are: a To characterise immunological responses in blood plasma and in circulating immune cell subsets of healthy volunteers and people with SPMS after TSPO functional changes induced by challenge ligand binding. b To explore the potential dependence of these pharmacodynamic responses on variation at rs6971 (a common polymorphism influencing ligand binding affinities in the TSPO protein) in the TSPO gene.