Pathophysiology of graft-versus-host disease.

Complications of allogeneic hematopoietic stem cell transplantation (HSCT) remain barriers to its wider application for a variety of diseases. Graft-versus-host disease (GVHD) is the major cause of morbidity and mortality following allogeneic HSCT. GVHD can be considered an exaggerated, undesirable manifestation of a normal inflammatory mechanism, in which donor lymphocytes encounter foreign antigens in a milieu that fosters inflammation. Recent advances in the study of cytokine networks, chemokine gradients, and the direct mediators of cellular cytotoxicity have led to improved understanding of this complex syndrome. The pathophysiology of acute GVHD can be considered as a three-step process in which the innate and adaptive immune systems interact: (1) tissue damage to the recipient by the radiation/chemotherapy pretransplant conditioning regimen; (2) donor T-cell activation and clonal expansion; and (3) cellular and inflammatory factors. Here we review the immunologic interactions that cause clinical GVHD and discuss the risk factors and prophylactic strategies for acute GVHD according to this model.