Pathogenesis and prevention of graft-versus-host disease

Abstract

Graft-versus-host disease (GVHD) has been the primary limitation to the wider application of allogeneic bone marrow transplantation. GVHD occurs when donor T cells react to host antigens on antigen-presenting cells and attack host tissues, with sequential activation of donor T cells and monocytes and macrophages. The net effects of dysregulated cytokine production in this complex system are the severe inflammatory manifestations that we recognize as clinical acute GVHD. Chronic GVHD, which occurs later than day 100 after bone marrow transplant, has distinctive clinical and pathologic manifestations that mimic autoimmune disease, although its exact pathogenesis remains ambiguous. Current experimental approaches to preventing acute GVHD include induction of tolerance either by inducing mixed chimerism with reduced conditioning or by blunting the initial interactions of donor T cells through the blockade of costimulatory molecules, thereby interrupting the undesirable inflammatory aspects of GVHD.