title: Pathophysiology of acute graft-versus-host disease.
abstract: Graft-versus-host disease (GVHD) has been the primary limitation to the wider application of allogeneic bone marrow transplantation (BMT). The pathophysiology of acute GVHD is complex and can be conceptualized to be a three-step process based on murine studies. In step 1, the conditioning regimen leads to the damage and activation of host tissues and induces the secretion of inflammatory cytokines. As a consequence, the expression of MHC antigens and adhesion molecules is increased enhancing the recognition of host alloantigens by donor T cells. Donor T-cell activation in step 2 is characterized by donor T cell interaction with host APCs and subsequent proliferation, differentiation and secretion of cytokines. Cytokines such as IL-2 and IFN-gamma enhance T-cell expansion, induce cytotoxic T cells (CTL) and natural killer (NK) cell responses and prime additional mononuclear phagocytes to produce TNF-alpha and IL-1. These inflammatory cytokines in turn stimulate production of inflammatory chemokines, thus recruiting effector cells into target organs. In step 3, effector functions of mononuclear phagocytes are triggered via a secondary signal provided by lipopolysaccharide (LPS) that leaks through the intestinal mucosa damaged during step 1. This mechanism may result in the amplification of local tissue injury and further promotion of an inflammatory response, which, together with the CTL and NK components, leads to target tissue destruction in the transplant host. The following review discusses the three-step process of the pathophysiology of experimental acute GVHD.
authors.affiliation: Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109-0942, USA. reddypr@umich.edu
authors.forename: Pavan
authors.initials: P
authors.lastname: Reddy
mesh_terms: D000208:Acute Disease; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology; D006086:Graft vs Host Disease / Q000503:physiopathology*; D006801:Humans; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous