Advances in predicting acute GVHD

Abstract

Acute graft-versus-host disease (GVHD) is a leading cause of non-relapse mortality following allogeneic haematopoietic cell transplantation. Attempts to improve treatment response in clinically-established GVHD have not improved overall survival, often due to the increased risk of infectious complications. Alternative approaches to decrease GVHD-related morbidity and mortality have focused on the ability to predict GVHD prior to clinical manifestation in an effort to provide an opportunity to abort GVHD development, and to gain new insights into GVHD pathophysiology. This review outlines the research efforts to date that have identified clinical and laboratory-based factors that are predictive of acute GVHD and describes future directions in developing algorithms that will improve the ability to predict the development of clinically relevant GVHD.

Figure 1

Pathophysiology of acute graft-versus-host disease. During the first phase (I), recipient conditioning regimen damages patient tissues and causes release of inflammatory cytokines such as TNF-α, IL-1 and IL-7, which leads to activation of host antigen-presenting cells (APCs). In the second phase (II), host APCs activate mature donor cells through IL-12 and IL-23 to produce T helper cell type 1 (Th1) cytokines, such as IL-2, IL-6 and IFN-γ. The synthesis of inflammatory cytokines is partly inhibited by IL-10. Activated Th1 cells induce increased indoleamine 2,3-dioxygenase (IDO) secretion from host APCs through IFN-γ secretion, thus stimulating immunotolerizing Tregs. IFN-γ also stimulates mononuclear cells to secrete inflammatory cytokines, such as IL-1 and TNF-α. (III) Th1 cells promote proliferation and differentiation of activated cytotoxic T lymphocytes (CTLs) and stimulate Natural Killer (NK) cells, which, in turn, induce apoptosis. Lipopolysaccharide (LPS) and bacterial cell wall components that have leaked through the damaged intestinal mucosa stimulate mononuclear cells through interactions with NOD2 and other innate immunity proteins, thus triggering additional inflammatory cytokine production causing apoptosis.