Graft-versus-Host Disease Signaling

Graft-versus-host disease (GVHD) pathophysiology occurs in a three-step process: The first step involves tissue damage caused due to treatment regimen of chemotherapy and/or irradiation. Inflammatory cytokines like TNF-α, IL-1 and IL-6 are secreted by the damaged tissue. Subsequently, increased expression of MHC antigens results in donor T cell activation.The second step, donor Th1 cell activation, is characterized by secretion of IL-2 and IFNγ. IL-2 activates donor cytotoxic T lymphocytes (CTLs) while IFNγ activates donor NK cells and macrophages. LPS, which leaks through damaged intestinal mucosa also stimulates macrophages to secrete cytotoxic molecules.The third step is the effector phase where activated CTL and NK cells mediate cytotoxicity against target host cells through Fas-Fas ligand interactions and perforin-granzyme B. During this phase, macrophages also destroy host cells via the secretion of cytotoxic molecules.