A new biology of clinical outcome in immune-mediated disease

Western medicine has developed by classifying disease into defined diagnostic categories. It is disease course after diagnosis, however, that determines a patient’s outcome, and the factors driving this variable prognosis have been largely ignored. We have focused on uncovering the biology underlying clinical outcome in immune-mediated disease. We have identified two CD8 T-cell transcription signatures that are associated with outcome but not diagnosis in four important immune-mediated diseases (Nat Med 2010, JCI 2011), and found that the signature associated with poor outcome is characterized by CD8 T cell “exhaustion” (Nature 2015). Genetic studies confirmed that pathways underlying prognosis are distinct from those underlying disease susceptibility (Cell 2013). We will explore this “biology of prognosis”. Our goals are to: 1) understand the biological basis of the CD8 T-cell transcription signature that determines prognosis. This will use in vitro and human in vivo studies, alongside genetic and epigenetic analyses informing our understanding of the mechanisms of prognosis in immune-mediated disease, and allowing the refinement of biomarkers now entering the clinic. 2) develop approaches to modulate CD8 T-cell exhaustion to treat disease, by re-purposing existing drugs, defining their mechanisms of action, and testing key candidates drugs in vitro and in animal models.