Glucocorticoid and glycolysis inhibitors cooperatively abrogate acute graft-versus-host disease

Science China Press

This study was designed by Professor. Yuan Kong (Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease) and Professor. Xiao-Jun Huang (Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease). Although allogeneic haematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for hematopoietic disorders, aGvHD remains a major complication after allo-HSCT. GCs are the standard first-line therapy for acute graft-versus-host disease (aGvHD), but nearly 50% of aGvHD patients have no response to GCs. The role of T cell metabolism in murine aGvHD was recently reported. However, whether GCs and metabolism regulators could cooperatively suppress T cell alloreactivity and ameliorate aGvHD remains to be elucidated.

In the current study, increased glycolysis, characterized by elevated 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), and higher rates of glucose consumption and lactate production were found in T cells from aGvHD patients. Genetic upregulation of PFKFB3 induced T cell proliferation and differentiation into proinflammatory cells. In a humanized mouse model, PFKFB3-overexpressing or PFKFB3-silenced T cells aggravated or prevented aGvHD, respectively. Importantly, their integrated data from patient samples in vitro, in a humanized xenogeneic murine model of aGvHD and graft-versus-leukaemia (GVL) demonstrate that GCs combined with a glycolysis inhibitor could cooperatively reduce the alloreactivity of T cells and ameliorate aGvHD without loss of GVL effects.

Together, the current study indicated that glycolysis is critical for T cell activation and induction of human aGvHD. Therefore, the regulation of glycolysis offers a potential pathogenesis-oriented therapeutic strategy for aGvHD patients. GCs combined with glycolysis inhibitors promises to be a novel first-line combination therapy for aGvHD patients.

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