Current and future approaches for control of graft-versus-host disease.

Graft-versus-host disease (GVHD), both acute and chronic, remains one of the major barriers to improving outcomes after allogeneic stem cell transplantation. The pathophysiology of GVHD is complex and incompletely understood. GVHD is believed to arise from the interaction of: tissue damage and proinflammatory cytokines causing activation of antigen-presenting cells (APCs, donor T-cell activation by APCs and cytokines and host tissue injury by effector T lymphocytes and proinflammatory cytokines. There is also a role for additional lymphocyte subtypes (naive and memory T cells, regulatory T cells, natural killer T cells and B cells) in GVHD pathogenesis. Strategies to improve donor-recipient HLA match, and to minimize conditioning toxicity, cytokine release and APC and effector T-lymphocyte activation, will likely improve prophylaxis of acute (and possibly chronic) GVHD. Therapy of established acute and chronic GVHD is still heavily dependent on corticosteroids, despite their limited efficacy and considerable toxicity. Novel agents (and/or combinations of agents) comprising pharmacologic, biologic and cellular therapies targeting specific steps or subsets involved in immune activation will likely comprise future advances in GVHD control. This article reviews the current state of knowledge regarding the prevention and treatment of acute and chronic GVHD. Novel approaches currently undergoing evaluation are also highlighted.