Thesis Myrddin Verheij

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment option for patients with malignant- and non-malignant blood disorders. One of the main limitations of this treatment is acute graft- versus- host disease (GvHD), a potentially severe complication in which donor lymphocytes target tissues of the host for destruction. Tissue damage and inflammation induced by the underlying disease of patients and the conditioning regimen that they receive plays an important role in the development of acute GvHD. The studies presented in this thesis aim to advance the understanding of the role of various mediators of tissue damage and inflammation in the development of acute GvHD with the goal of improving treatment strategies for patients. We show that damage-associated molecular patterns (DAMPs) are involved in acute GvHD development. We found that the induction of heme oxygenase-1 (HO-1), an intracellular enzyme that catabolizes the breakdown of cell-free heme (a potent DAMP), seems to provide protection against acute GvHD and that cell-free DNA is elevated in patients at the time of acute GvHD diagnosis. These findings warrant further research into HO-1 induction for the prevention and treatment of acute GvHD in humans and the use of cell-free DNA as an additional biomarker for diagnosis. Finally, we show that a relatively high number of innate lymphoid cells (ILC) present in hematopoietic cell grafts significantly reduces the incidence of acute GvHD in allogeneic HSCT recipients, indicating that adoptive transfer of ILC in this patient group is an interesting treatment strategy to explore further.