Circadian fluctuation of soluble CD26 dictates the impact of the timing of cord blood transplantation on acute graft-versus-host disease

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a cornerstone treatment for many malignant and nonmalignant hematological diseases. Our recent research demonstrated that early-day stem cell infusions significantly reduce the incidence and severity of acute graft-versus-host disease (aGVHD) following allo-HSCT using fresh grafts. However, the impact of infusion timing on aGVHD in allo-HSCT with cryopreserved grafts such as unrelated cord blood (UCB) remains unclear. Here, we show that early-morning cord blood infusions significantly reduce aGVHD severity and improve survival. We further found that circadian variations in cytokines, particularly soluble CD26 (sCD26), are correlated with the severity of aGVHD. Inhibiting the enzymatic activity of sCD26 with Sitagliptin significantly mitigated aGVHD and improved survival in late-infused female mice. Our study indicates that scheduling UCB transplantation in the early morning could be a simple and effective prophylactic strategy for aGVHD and that inhibiting sCD26 could be a promising therapeutic approach for late infusions.