The pathophysiology of acute graft-versus-host disease.
The pathophysiology of acute graft-versus-host disease (GVHD) is a complex process that can be conceptualized in three phases. In the first phase, high-dose chemoradiotherapy causes damage to host tissues, including a self-limited burst of inflammatory cytokines such as tumor necrosis factor (TNF)-alpha and interleukin 1. These cytokines activate host antigen-presenting cells (APCs). In the second phase, donor T-cells recognize alloantigens on host APCs. These activated T-cells then proliferate, differentiate into effector cells, and secrete cytokines, particularly interferon (IFN)-gamma. In the third phase, target cells undergo apoptosis mediated by cellular effectors (eg, donor cytotoxic T-lymphocytes) and inflammatory cytokines such as TNF-alpha. TNF-alpha secretion is amplified by stimuli such as endotoxin that leaks across damaged gastrointestinal mucosa injured by the chemoradiotherapy in the first phase. TNF-alpha and IFN-gamma cause further injury to gastrointestinal epithelium, causing more endotoxin leakage and establishing a positive inflammatory feedback loop. These events are examined in detail in the following review.
Ferrara
James L M
JL
University of Michigan Cancer Center, Bone Marrow Transplant Program, Ann Arbor, Michigan, USA. ferrara@umich.edu
Cooke
Kenneth R
KR
Teshima
Takanori
T
D000208:Acute Disease; D000818:Animals; D017209:Apoptosis / Q000276:immunology; D016207:Cytokines / Q000276:immunology; D006086:Graft vs Host Disease / Q000209:etiology / Q000276:immunology / Q000473:pathology*; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects; D006801:Humans; D013601:T-Lymphocytes / Q000276:immunology; D019172:Transplantation Conditioning / Q000009:adverse effects
D016207:Cytokines