Hematopoietic stem cell therapy for inflammatory bowel diseases

Inflammatory bowel diseases (IBD) are chronic debilitating inflammatory disorders of potentially any part of the gastrointestinal tract, leading to various intestinal but also extra-intestinal symptoms. It is thought that dysregulation of the normally controlled immune response to commensal bacteria in genetically susceptible patients drives the disease. Although medical therapy for IBD has improved due to an extensive repertoire of immunosuppressive drugs and the introduction of anti tumor necrosis factor-α (TNFα) compounds, the clinical course of the disease cannot be adequately controlled in a substantial group of patients. More than half of the patients require one or more surgical resections during the course of the disease. Therefore, there is an unmet need for more effective therapeutic strategies. Evidence that hematopoietic stem cell transplantation (HSCT) would be an effective treatment for autoimmune diseases firstly came from several animal models and from incidental case reports on HSCT recipients with coexistent autoimmune disease. Already more than 15 years ago a case report on the positive effect of HSCT on active IBD was published, followed by many others showing improvement of the clinical course of disease after HSCT indicated for other diseases. In the last couple of years, various cases have been reported of successful remission induction of patients with (therapy refractory) Crohn's disease (CD) by means of an autologous HSCT. The most extensive experience on autologous HSCT applied specifically for CD has been reported by the group of Oyama. All treated patients went into remission with a Crohn's Disease Activity Index (CDAI) score of <150. There was no inpatient mortality and neutropenic fever was the most important complication. Recently published long-term follow follow-up data showed a clinical relapse-free survival of 57% at 3 years and 19% at 5 years. The percentage of patients in remission (CDAI<150), steroid free, or medication free at any post-transplant evaluation interval over 5 years post-transplant was 70%, 80% and 60%, respectively. Although the observed benefit is remarkable, the exact mechanism behind this =resetting' of the immune system needs to be elucidated. Although the prolonged T cell depletion will probably add to the therapeutic benefit, the thymus most likely plays a dominant role in resetting the T cell repertoire in IBD patients. This chapter will review the evidence for HSCT for IBD and discuss potential mechanisms of HSCT important for clinical benefit.