Allogeneic 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.

The authors have declared no competing interest.

Cheng Zhan is supported by grants from the Research Funds of Center for Advanced Interdisciplinary Science and Biomedicine of IHM (QYPY20220018), the National Natural Science Foundation of China (32271063, 31822026, 31500860), and the National Science and Technology Innovation 2030 Major Project of China (2021ZD0203900). Xiaoyu Zhu is supported by grants from the National Natural Science Foundation of China (82270223), Anhui Provincial Department of Education Scientific Research Project (2023AH010079) and Anhui Provincial Natural Science Foundation (2308085J09).

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Ethics Committee of the First Affiliated Hospital of the University of Science and Technology of China (USTC) gave ethical approval for this work (REC reference: 2023/RE/327). The patients or a guardian provided informed consent before transplantation for the use of their data for research, in accordance with the Declaration of Helsinki.

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