New approaches to better understand an old treatment regimen - molecular, cellular and live intravital imaging studies on glucocorticoid therapy of experimental autoimmune encephalomyelitis as a model of multiple sclerosis

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Treatment of acute relapses with glucocorticoids (GCs) is a mainstay in multiple sclerosis (MS) therapy. Induction of T cell apoptosis is currently believed to be one of the central mechanisms of this regimen but our recent findings challenge this view. GCs ameliorate experimental autoimmune encephalomyelitis (EAE) in mice that are refractory to apoptosis, raising the question as to which mechanisms are then responsible for therapeutic success. Preliminary in vitro data point towards a profound effect of GCs on leukocyte motility. By combining genetically modified mice not previously investigated in this context with molecular and immunological analyses and new techniques such as intravital 2-photon laser scanning microscopy we will determine the influence of GC treatment on the locomotion of immune cells directly within the lymphatic organs and the CNS of living mice. In parallel, we will investigate the role of well-established and potentially new GC actions on cytokine production, T cell priming, transmigration, morphology and the formation of the immunological synapse. Lastly, we plan to initiate first experiments to validate our findings using human T cells. In summary, the combination of new mouse models with molecular analyses and state-of-the-art imaging techniques should place us in a position to address crucial aspects of GC action such as the importance of apoptosis induction, leukocyte motility and trafficking as well as T cell reactivation.