RT info:eu-repo/semantics/article
T1 Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development
A1 Herrero Sánchez, María del Carmen
A1 Rodríguez Serrano, Concepción
A1 Almeida Parra, Julia
A1 San Segundo Payo, Laura
A1 Inogés Sancho, Laura
A1 Santos-Briz Terrón, Ángel
A1 García Briñón, Jesús
A1 Corchete Sánchez, Luis Antonio
A1 San Miguel Izquierdo, Jesús F.
A1 Cañizo Fernández-Roldán, Consuelo del
A1 Blanco Durango, Belén
K1 Cell transplantation
K1 Trasplante de células
K1 Graft versus host disease
K1 Immunology
K1 Cell Biology
K1 3201.01 Oncología
K1 3205.04 Hematología
AB 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 significantlyimproved 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.
PB BioMed Central (BMC)
SN 1756-8722
YR 2016
FD 2016
LK https://uvadoc.uva.es/handle/10324/55154
UL https://uvadoc.uva.es/handle/10324/55154
LA eng
NO Journal of Hematology & Oncology, 2016, Vol. 9, Nº. 113, 15 pp.
NO Producción Científica
DS UVaDOC
RD 12-sep-2024