Epithelial injury in acute graft-versus-host disease of the gut

Abstract

Every year about 75 children in the Netherlands undergo an allogeneic stem cell transplantation (SCT) as an ultimate treatment for leukemia for instance. Unfortunately, often the complication acute Graft-versus-Host disease (GvHD) occurs, in which donor immune cells recognize the patients’ tissue as foreign and launch an extensive inflammatory attack. Due to the risk of dehydration, malnutrition and infection GvHD of the gut is especially associated with high morbidity and mortality. GvHD treatment aims to suppress the overactive immune system with corticosteroids (CS), but in almost half of patients, such as children in the Netherlands (Chapter 2), treatment fails, and patients develop steroid-refractory (SR-)GvHD. The development of new therapies that do not exclusively focus on the immune system is crucial. In this thesis, we show that intestinal epithelial damage plays an important role in the development of GvHD (Chapter 7). Using mouse models and culture models with organoids and immune cells, we simulated certain aspects of GvHD. Firstly, we found that epithelial damage caused by chemotherapy before SCT attracted donor T cells and stimulated their activation (Chapter 4). Galectin (gal)-9 released by the damaged epithelium was involved in both processes, and was also elevated in the serum of children that eventually developed GvHD. Depending on its exact role in the pathophysiology, gal-9 could be a new target for GvHD prevention or treatment. Secondly, we found that donor T cell-derived interferon-gamma (IFNg) directly targets intestinal stem cells (ISCs) in GvHD (Chapter 5). The ISCs could be protected by inhibiting IFNg signaling at the epithelial level with ruxolitinib. Currently ruxolitinib is only a registered treatment for adults with SR-GvHD, but earlier application or even preventative treatment could be promising. Thirdly, we discovered that CS used in GvHD treatment actually limit the regeneration of the damaged intestinal epithelium (Chapter 6). Treatment with interleukin-(IL)-22 stimulated the ISCs to recover the gut lining, even in the presence of CS. This is an important finding, as in current trials with adults, IL-22 is applied alongside CS. Finally, we efficiently enriched for and subsequently identified viruses in the feces of children suspected of gut GvHD (Chapter 3). When applied to larger cohorts of patients, this method will shed light on associations between gut viruses and outcomes of GvHD patients, and possible treatment options therein. In conclusion, there is an urgent need for new therapies for SR-GvHD, and multiple targets can be found in the concept of intestinal epithelial damage during SCT. Further research using our disease models and testing our findings in human trials will hopefully lead to a better future for patients with GvHD.