Cytokine dysregulation in acute graft-versus-host disease

Graft versus host disease (GVHD) remains the principal complication limiting the wider application of allogeneic bone marrow transplantation (BMT). Advances in basic immunology during the last decade have demonstrated how interactions between immunologically competent cells are governed by cytokines, and much recent research has focused on the roles of these mediators in the pathogenesis of acute GVHD. This article will review current evidence that dysregulated cytokine production can be considered a cascade of sequential activation of T-cells and monocytes that is responsible for many of the manifestations of acute GVHD. We suggest that cytokine dysregulation can be divided into three phases. Phase 1 is initiated by the conditioning of the host, which induces inflammatory processes in recipient tissues. Donor T-cell activation by host alloantigens and subsequent cytokine secretion in Phase 2 is facilitated by the consequences of Phase 1. The T-cell derived cytokines of Phase 2 activate distal inflammatory meditators which, together with T and NK-cell-mediated cytotoxicity, produce the systemic morbidity of GVHD-associated immunosuppression in Phase 3. Data from both experimental and clinical studies involving cytokines and their blockade in the prevention or treatment of GVHD will be reviewed.