Approaches for the prevention of graft-versus-host disease following hematopoietic cell transplantation

Abstract

Allogeneic hematopoietic cell transplantation (HCT) is an important therapeutic option for malignant and non-malignant diseases, but the more widespread application of the therapy remains limited by the occurrence of graft versus host disease (GVHD). GVHD results from immune-mediated injury by donor immune cells against tissues in the HCT recipient, and can be characterized as acute or chronic depending on the time of onset and site of organ involvement. The majority of efforts have focused on GVHD prevention. Calcineurin inhibitors are the most widely used agents and are included in almost all regimens. Despite current prophylaxis strategies, 40-70% of patients remain at risk for developing GVHD. Herein, we review standard and emerging therapies used in GVHD management.

Keywords: GVHD; acute; calcineurin inhibitors; chronic; hematopoietic stem cell transplantation; prophylaxis; treatment.

Figure 1

Mechanisms of actions of agents to prevent and/or treat GVHD. The medications and their cellular targets are illustrated. Infusions of T regulatory cells (T_reg) and mesenchymal stem cells (MSC) are depicted extracellularly. Abbreviations: ADA, adenosine deaminase; ATG, anti-thymocyte globulin; CCR5, C-C chemokine receptor 5; CTLA4, cytotoxic T lymphocyte antigen 4; Cy, cyclophosphamide; DHFR, dihydrofolate reductase; FKBP12, FK506 binding protein 12; GVHD, graft-versus-host disease; HAT, histone acetyltransferase; HDAC, histone deacetylase inhibitor; HMG CoA reductase, 3-hydroxy-3-methyl-glutaryl coenzyme A reductase; iCasp9, inducible caspase 9; IκB, nuclear factor of kappa light polypeptide gene enhancer in B cells inhibitor; IL, interleukin; IMPDH, inosine monophosphate dehydrogenase; MHC II, major histocompatibility class II; mTORC, mammalian target of rapamycin complex; MTX, methotrexate; NFATc, nuclear factor of activated T-cell cytoplasmic; TNFR, tumor necrosis factor receptor.