Optimizing stem cell infusion timing in the prevention of acute graft-versus-host disease

Abstract

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. Here, we show in patients and murine models that the circadian timing of stem cell infusion dictates the development of aGVHD. Early-infused patients exhibit a significantly lower incidence and severity of aGVHD, as well as improved survival. We observed time-of-day variations in the levels of cytokines, especially IL-1α, which controls donor T cell responses after transplantation. The levels of IL-1α in patients were strongly associated with the development of aGVHD. Furthermore, preclinical results showed that the administration of IL-1α neutralizing antibodies markedly alleviated aGVHD and increased survival. Our study suggests that scheduling stem cell infusions early in the day could be a simple yet transformative intervention for preventing aGVHD.

Keywords: IL-1α; T cell responses; acute graft-versus-host disease; allogeneic hematopoietic stem cell transplantation; circadian rhythm; haplo-identical donors; matched sibling donors; stem cell infusion.