image: Schematic illustration of T cell glycolysis in GvHD, and GCs and glycolysis inhibitors cooperatively abrogate aGvHD. MP, methylprednisolone, which is one of glucorticosteroids; 3PO, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one, which is a glycolysis inhibitor. view more
Credit: ©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.
Journal
Science China Life Sciences