The transplantation of healthy hematopoietic stem cells into a patient with aplastic anemia or leukemia is potentially curative therapy, but the development of graft-versus-host disease (GVHD)—which often occurs even when the donor and recipient are siblings fully matched at the HLA loci—significantly limits survival. The first descriptions of GVHD following allogeneic bone marrow transplant in humans were made in the 1960s. Significant strides in prophylaxis of GVHD have been made over the past four decades by the use of pharmacologic agents such as methotrexate and cyclosporine and by manipulation of the donor cell inoculum to limit the infusion of effector donor lymphocytes. However, given the extensive clinical observations and investigations on the nature of this complication, it is remarkable that the diagnosis of GVHD is still clinically challenging and that this complication continues to pose a formidable obstacle to successful allogeneic hematopoietic stem cell transplantation (HSCT). On the other hand, patients with GVHD have improved leukemia-free survival (the graft-versus-leukemia (GVL) effect) and this graft-versus-malignancy (GVM) effect, a beneficial by-product of the alloreac-tivity of the donor cells, may extend to lymphomas, myeloma, and even solid tumors.1-4 Thus, a major question in HSCT biology is how to preserve a GVM effect while eliminating GVHD. This chapter will review some of the critical issues in the clinical manifestations and pathobiology of GVHD, including the results of recent investigations using an in vitro lymphocyte-skin adhesion assay to better define the mechanisms of GVHD. Advances during the past decade in the prevention and treatment of GVHD including recent evidence for a role of cellular modulation of GVHD will also be reviewed.

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