Challenges and opportunities targeting mechanisms of epithelial injury and recovery in acute intestinal graft-versus-host disease

Despite advances in immunosuppressive prophylaxis and overall supportive care, gastrointestinal (GI) graft-versus-host disease (GVHD) remains a major, lethal side effect after allogeneic hematopoietic stem cell transplantation (allo-HSCT). It has become increasingly clear that the intestinal epithelium, in addition to being a target of transplant-related toxicity and GVHD, plays an important role in the onset of GVHD. Over the last two decades, increased understanding of the epithelial constituents and their microenvironment has led to the development of novel prophylactic and therapeutic interventions, with the potential to protect the intestinal epithelium from GVHD-associated damage and promote its recovery following insult. In this review, we will discuss intestinal epithelial injury and the role of the intestinal epithelium in GVHD pathogenesis. In addition, we will highlight possible approaches to protect the GI tract from damage posttransplant and to stimulate epithelial regeneration, in order to promote intestinal recovery. Combined treatment modalities integrating immunomodulation, epithelial protection, and induction of regeneration may hold the key to unlocking mucosal recovery and optimizing therapy for acute intestinal GVHD.