Optimizing Stem Cell Infusion Timing in the Prevention of Acute Graft versus Host Disease

Abstract

SUMMARYAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is a cornerstone treatment for a broad spectrum of malignant and nonmalignant hematological disorders. However, the success of allo-HSCT is often overshadowed by acute graft-versus-host disease (aGVHD), a life-threatening complication with limited preventive options. Here, we found that the incidence and severity of aGVHD after allo-HSCT are highly dependent on the circadian timing of stem cell infusion. The incidence rate of aGVHD in patients decreased by approximately 50% for early infusion (before 2:00 pm) compared to later infusion (after 2:00 pm). Early-infused patients also experienced significantly lower three-year transplant-related mortality and improved GVHD-free, relapse-free survival. Animal studies using an aGVHD mouse model show that this improvement is mainly due to the recipient’s rhythm rather than the donor’s. Mechanistically, compared with late infusions, early infusions significantly reduced the levels of the pro-inflammatory cytokine IL-1α following the conditioning regimen and subsequently suppressed T-cell activation and differentiation after transplantation. Our study suggests that scheduling stem cell infusions early in the day could be a simple yet transformative intervention for the prevention of aGVHD.