Recent advances in the pathophysiology of acute and chronic graft-versus-host disease.

Acute and chronic graft-versus-host disease (GVHD) remains major obstacles to the success of allogeneic hematopoietic cell transplantation (allo-HCT). Recent advances in experimental models and clinical studies have refined our understanding of the cellular and molecular mechanisms that drive GVHD and revealed new therapeutic opportunities. Emerging evidence indicates tissue tolerance mediated by epithelial regeneration from tissue stem cells plays a protective role against GVHD. Furthermore, we recently found tissue stem cells persisting after acute GVHD have epigenetic changes that lead to GVHD exacerbation at GVHD flare. Chronic GVHD develops through a more complex immunopathology involving T and B cells, macrophages, and fibroblasts. Disrupted immune reconstitution, including impaired thymic tolerance, aberrant B-cell activation driven by BAFF, and defective regulatory T-cell recovery, contributes to sustained alloimmunity. T-cell exhaustion has recently been recognized as a central checkpoint: While terminal exhaustion promotes tolerance, early calcineurin inhibitor (CNI) administration suppresses terminal exhaustion and drives the accumulation of transitory exhausted T cells that mediate chronic GVHD while preserving graft-versus-leukemia (GVL) activity. Post-transplant cyclophosphamide (PTCy)-based platforms highlight how delayed CNI initiation reduces chronic GVHD by permitting donor T cells to undergo exhaustion.