Figure 1.

Overview of the pathophysiology of graft-versus-host disease. The pathophysiology of graft-versus-host disease (GVHD) involves five steps. (1) Conditioning regimen with chemotherapy and/or total body irradiation, which results in the release of pro-inflammatory cytokines that affects host-antigen presenting cells (APCs) by increasing their maturation and the expression of co-stimulatory molecules and cytokines, which in turn fuel donor alloreactive T cells. (2) T cell recognition followed by T cell receptor (TCR) ligation, (the first signal to the donor T cells) and engagement of stimulatory molecules (the second signal to the donor T cells). Both of these signals are required for full T cell activation and subsequent expansion. (3) Proliferation and differentiation of alloreactive donor T cells, followed by (4) trafficking of alloreactive T cells toward GVHD target organs (e.g., skin, gut, liver, lungs), a process that is controlled by chemokines and adhesion molecules. Inflamed and injured tissues produce chemokines, which also result in the recruitment of neutrophils, natural killer (NK) cells, and monocytes to GVHD organs and contribute to the GVHD pathology. (5) The effector phase notes for the destruction of host tissue by effector molecules such as Fas ligand (FasL), perforin, granzymes, interferon-gamma (IFN-γ), tumor necrosis factor (TNF), that induce a cytokine storm that drives the whole GVHD process.