Concise review: acute graft-versus-host disease: immunobiology, prevention, and treatment

Abstract

Graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplant (AHSCT) associated with significant morbidity and mortality. This review focuses on the pathophysiology, clinical features, prevention, and treatment of acute GVHD. Specifically, we explain how new discoveries in immunology have expanded our understanding of GVHD, in which tissue damage from chemotherapy or radiation results in cytokine release, which activates T cells, resulting in proliferation and differentiation, trafficking to target organs, and tissue destruction and inflammation. Insights into the mechanisms of this disease relate directly to the development of preventive strategies and therapies, such as immunosuppression, T-cell depletion, calcineurin inhibitors, CCR5 antagonists, gut decontamination, extracorporeal photopheresis, and more. We also discuss how GVHD affects the gut, liver, and skin, as well as diagnosis, grading, and scoring. We end by examining future directions of treatment, including new immunomodulators and biomarkers. Understanding the immunobiology of GVHD and developing effective preventions and treatments are critical to the continuing success of AHSCT.

Figure 1.

Pathophysiology of graft-versus-host disease (GVHD). (1) Chemotherapy and radiation cause tissue damage, producing proinflammatory cytokines, resulting in (2) T-cell activation through APC-T-cell interaction via MHC-T-cell receptor binding and costimulatory signals, leading to (3) expansion and differentiation into various subtypes of T cells, which (4) traffic through blood vessels to target organs, where they (5) cause tissue destruction and recruitment of other inflammatory cells through pathways such as perforin/granzyme and cytokine release. These inflammatory cells and cytokines can further propagate the cycle of GVHD. This process is internally regulated by Tregs as well as thymic deletion of alloreactive T cells (inside of circle); exogenous means of treating GVHD include inhibitors of inflammation and cytokines, immune checkpoint modulators, calcineurin inhibitors, and CCR5 inhibitors (outside of circle). Abbreviations: APC, antigen-presenting cell; CCR5, chemokine receptor type 5; IFNγ, interferon γ; MHC, major histocompatibility complex; T_CM, central memory T cell; T_EM, effector memory T cell; TNFα, tumor necrosis factor α; TRAIL, tumor necrosis factor-related apoptosis-inducing ligand; Treg, regulatory T-cell.