Sphingosine 1-phosphate modulation and immune cell trafficking in inflammatory bowel disease

Immune cell trafficking is a critical element of the intestinal immune response, both in homeostasis and in pathological conditions associated with inflammatory bowel disease (IBD). This process involves adhesion molecules, chemoattractants and receptors expressed on immune cell surfaces, blood vessels and stromal intestinal tissue as well as signalling pathways, including those modulated by sphingosine 1-phosphate (S1P). The complex biological processes of leukocyte recruitment, activation, adhesion and migration have been targeted by various monoclonal antibodies (vedolizumab, etrolizumab, ontamalimab). Promising preclinical and clinical data with several oral S1P modulators suggest that inhibition of lymphocyte egress from the lymph nodes to the bloodstream might be a safe and efficacious alternative mechanism for reducing inflammation in immune-mediated disorders, including Crohn's disease and ulcerative colitis. Although various questions remain, including the potential positioning of S1P modulators in treatment algorithms and their long-term safety, this novel class of compounds holds great promise. This Review summarizes the critical mediators and mechanisms involved in immune cell trafficking in IBD and the available evidence for efficacy, safety and pharmacokinetics of S1P receptor modulators in IBD and other immune-mediated disorders. Further, it discusses potential future approaches to incorporate S1P modulators into the treatment of IBD.