Glucocorticoid and glycolysis inhibitors cooperatively abrogate acute graft-versus-host disease.
Sci China Life Sci
; 66(3): 528-544, 2023 03.
Article
em En
| MEDLINE
| ID: mdl-36166182
ABSTRACT
Although glucorticosteroids (GCs) are the standard first-line therapy for acute graft-versus-host disease (aGvHD), 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. 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, our 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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Base de dados:
MEDLINE
Assunto principal:
Transplante de Células-Tronco Hematopoéticas
/
Doença Enxerto-Hospedeiro
Limite:
Animals
/
Humans
Idioma:
En
Revista:
Sci China Life Sci
Assunto da revista:
BIOLOGIA
/
CIENCIA
Ano de publicação:
2023
Tipo de documento:
Article
País de afiliação:
China