Understanding the alloresponse: new approaches to graft-versus-host disease prevention

Abstract

Graft-versus-host disease (GVHD) has been the primary limitation to the wider application of allogeneic bone marrow transplantation (BMT). GVHD occurs when donor T cells react to host antigens on antigen-presenting cells (APCs) and attack host tissues, with sequential activation of donor T cells and monocytes/macrophages. The net effects of dysregulated cytokine production in this complex system are the severe inflammatory manifestations that we recognize as clinical acute GVHD. Long-term outcomes are also adversely affected by chronic GVHD, which has distinctive clinical and pathologic manifestations that mimic autoimmune disease, although its exact pathogenesis remains ambiguous. The ultimate goal for preventing GVHD is the induction of specific tolerance to host antigens, thereby maintaining favorable aspects of donor immunity. Tolerance may be achieved by costimulatory blockade, deletion of activated cells, suppression by regulatory T cells, and immune deviation. This report will focus on these mechanisms as they relate to the pathophysiology of acute GVHD.