Crohn’s disease: Mucosal immunology and immune modulating therapy

Crohn’s disease (CD) and ulcerative colitis (UC) are debilitating chronic diseases that affect millions of people worldwide, profoundly impacting patient quality of life and incurring large costs in terms of treatment and lost productivity. While current interventions ameliorate disease symptoms, they do not provide a cure, and there is significant unmet medical need. Successful discovery and development of more effective CD therapies depends on a better understanding of the underlying mechanisms of disease, including how pro-inflammatory cells proliferate unchecked, and how the body’s own mechanisms might be enlisted to control inflammation. The studies presented in this thesis were undertaken to provide a better understanding of immunological parameters operational in CD. Current therapies target cytokines produced by pro-inflammatory immune cells and thereby reduce intestinal inflammation and induce remission of disease. Nevertheless not all patients respond to these therapies. Furthermore, among those responding initially, many patients fail subsequent efficacy of maintenance therapy. Starting a treatment for remission induction therapy is a matter of trial and error, since mechanisms predisposing or regulating non-response have not been elucidated. Moreover, the assessment of therapy efficacy is hampered by the lack of objective markers. To identify biomarkers for therapy response, this thesis describes in depth analyses on patients that respond and patients who do not respond to remission induction therapy. By the identification of differential gene expression and cytokine profiles between responders and non-responders novel insights for biomarkers and underlying mechanisms are obtained. These studies provide a path to development of better diagnostics predicting response to therapy.