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Título
Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development
Autor
Año del Documento
2016
Editorial
BioMed Central (BMC)
Descripción
Producción Científica
Documento Fuente
Journal of Hematology & Oncology, 2016, Vol. 9, Nº. 113, 15 pp.
Resumo
Background: Graft-versus-host disease (GvHD) remains the major obstacle to successful allogeneic hematopoietic stem cell transplantation, despite of the immunosuppressive regimens administered to control T cell alloreactivity. PI3K/AKT/mTOR pathway is crucial in T cell activation and function and, therefore, represents an attractive therapeutic target to prevent GvHD development. Recently, numerous PI3K inhibitors have been developed for cancer therapy. However, few studies have explored their immunosuppressive effect. Methods: The effects of a selective PI3K inhibitor (BKM120) and a dual PI3K/mTOR inhibitor (BEZ235) on human T cell proliferation, expression of activation-related molecules, and phosphorylation of PI3K/AKT/mTOR pathway proteins were analyzed. Besides, the ability of BEZ235 to prevent GvHD development in mice was evaluated. Results: Simultaneous inhibition of PI3K and mTOR was efficient at lower concentrations than PI3K specific targeting. Importantly, BEZ235 prevented naïve T cell activation and induced tolerance of alloreactive T cells, while maintaining an adequate response against cytomegalovirus, more efficiently than BKM120. Finally, BEZ235 treatment significantly
improved the survival and decreased the GvHD development in mice. Conclusions: These results support the use of PI3K inhibitors to control T cell responses and show the potential utility of the dual PI3K/mTOR inhibitor BEZ235 in GvHD prophylaxis.
Materias (normalizadas)
Cell transplantation
Trasplante de células
Graft versus host disease
Immunology
Cell Biology
Materias Unesco
3201.01 Oncología
3205.04 Hematología
ISSN
1756-8722
Revisión por pares
SI
Patrocinador
Asociación Española Contra el Cáncer (Proyecto AIOA110296BLAN).
Gerencia Regional de Salud de Castilla y León (Proyecto GRS 726/A13)
Gerencia Regional de Salud de Castilla y León (Proyecto GRS 726/A13)
Version del Editor
Propietario de los Derechos
© 2016 The Author(s).
Idioma
eng
Tipo de versión
info:eu-repo/semantics/publishedVersion
Derechos
openAccess
Aparece en las colecciones
Arquivos deste item
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