Graft-versus-host disease (GVHD) pathophysiology can be summerized in a three-step process. During step 1, the conditioning regimen (irradiation and/or chemotherapy) leads to damage, activation of host tissues and induction of inflammatory cytokines [tumour necrosis factor (TNF-alpha) and interleukin (IL-1)] secretion. Increased expression of major histocompatibility complex (MHC) antigens and adhesion molecules leads to enhancement of the recognition of host MHC and/or minor histocompatibility antigens by mature donor T cells.
Donor T-cell activation in step II is characterized by the predominance of Th1 cells and the secretion of IL-2 and IFN-gamma. These cytokines induce further T-cell expansion, induce cytotoxic T lymphocytes (CTL) and natural killer (NK) cells responses and prime additional mononuclear phagocytes to produce TNF-alpha and IL-1. Also, nitric oxide (NO) is produced by activated macrophages, and it may contribute to the tissue damage seen during step 3. Lipopolysaccharide (LPS), which leaks through the intestinal mucosa that was damaged during step 1, together with IFN-gamma, from step 2, further stimulate macrophages to secrete cytokines and NO. During step 3, the effector phase, activated CTL and NK cells mediate cytotoxicity against target host cells through Fas-Fas ligand interactions and perforin-granzyme B. |
Graft-versus-host disease - Reference pathway (KO)
