Acute graft-versus-host disease-challenge for a broader application of allogeneic hematopoietic cell transplantation

Allogeneic hematopoietic cell transplanation (aHCT) has been a successful treatment option for malignant disease based on the graft-versus-tumor effect. However, the overall clinical success of aHCT is impaired by the high morbidity and mortality caused by acute graft-versus-host disease (aGVHD). aGVHD can also be seen as the major limitation of aHCT for a broader clinical applicability of this treatment, particularly for non-malignant disease conditions. Recent murine studies have shed more light on the kinetics of aGVHD development by tracking donor T cells in vivo. These data define two functionally distinct stages in aGVHD pathogenesis taking place in different anatomical compartments. The aGVHD initiation phase is confined to T cell areas in secondary lymphoid organs in contrast to the later aGVHD effector phase at target sites. This temporal pattern may explain the clinical observation that when acute aGVHD is clinically overt, treatment with intensified immunosuppression often remains ineffective. This review will focus on the immune-pathogenesis of aGVHD, conventional and novel treatment strategies including the removal of naïve T cells, tolerance induction by mesenchymal stem cells, regulatory T cells, genetic manipulation of donor cells and the potential of memory T cells for improving immune reconstitution without aGVHD. A better understanding of the mechanisms involved in aGVHD pathogenesis might allow for a broader application of novel stem cell therapies.