Janus kinase inhibition in the treatment of inflammatory bowel disease

The aim of this thesis was to investigate Janus kinase (JAK) inhibition in the treatment of inflammatory bowel disease (IBD) from a translational perspective, reflecting both on JAK inhibition as a clinical treatment for IBD as well as on JAK inhibition as a modulator of immune responses in vitro and in experimental colitis. There are four JAK family members, JAK1 , JAK2, JAK3 and tyrosine kinase 2 (TYK2). Each JAK family member is involved in signalling of pro-inflammatory cytokines, key in the pathogenesis of IBD. We investigated how Janus kinase (JAK) inhibition affects immune responses during intestinal inflammation. We demonstrated that JAK1 selective inhibition is the major contributor in altering the innate immune response in vitro and in vivo, when compared to pan-JAK inhibition by tofacitinib. In addition we found that tyrosine kinase 2 (TYK2) drives pathogenic T cells in experimental colitis models. Lastly, we showed that treatment with tofacitinib and a JAK1 selective inhibitor induced histological response and remission in human IBD. The interest in the field of JAK inhibition as a therapeutic strategy in IBD is rapidly expanding, hopefully leading to additional treatment options for patients with therapy refractory disease.