RT info:eu-repo/semantics/article
T1 Treatment with bortezomib of human CD4+ T cells preserves natural regulatory T cells and allows the emergence of a distinct suppressor T-cell population
A1 Blanco Durango, Belén
A1 Perez Simon, José Antonio
A1 Sánchez Abarca, Luis Ignacio
A1 Caballero Velazquez, Teresa
A1 Gutierrez Cossio, Silvia
A1 Hernández Campo, Pilar
A1 Diez Campelo, María
A1 Herrero Sánchez, María del Carmen
A1 Rodríguez Serrano, Concepción
A1 Santamaría Quesada, Carlos
A1 Sánchez Guijo, Fermín
A1 Cañizo Fernández-Roldán, Consuelo del
A1 San Miguel Izquierdo, Jesús F.
K1 Cell Biology
K1 Graft versus host disease
K1 Cell transplantation
K1 Trasplante de células
K1 Medical microbiology
K1 Pharmacology
K1 3205.04 Hematología
K1 3207.13 Oncología
AB Background In vitro depletion of alloreactive T cells using the proteasome inhibitor bortezomib is a promising approach to prevent graft-versus-host disease after allogeneic stem cell transplantation. We have previously described the ability of bortezomib to selectively eliminate alloreactive T cells in a mixed leukocyte culture, preserving non-activated T cells. Due to the role of regulatory T cells in the control of graft versus host disease, in the current manuscript we have analyzed the effect of bortezomib in regulatory T cells.Design and Methods Conventional or regulatory CD4+ T cells were isolated with immunomagnetic microbeads based on the expression of CD4 and CD25. The effect of bortezomib on T-cell viability was analyzed by flow cytometry using 7-amino-actinomycin D staining. To investigate the possibility of obtaining an enriched regulatory T-cell population in vitro with the use of bortezomib, CD4+ T cells were cultured during four weeks in the presence of anti-CD3 and anti-CD28 antibodies, IL-2 and bortezomib. The phenotype of these long-term cultured cells was studied, analyzing the expression of CD25, CD127 and FOXP3 by flow cytometry, and mRNA levels were determined by RT-PCR. Their suppressive capacity was assessed in co-culture experiments, analyzing proliferation and IFN-γ and CD40L expression of stimulated responder T cells by flow cytometry.Results We observed that naturally occurring CD4+CD25+ regulatory T cells are resistant to the pro-apoptotic effect of bortezomib. Furthermore, we found that long-term culture of CD4+ T cells in the presence of bortezomib promotes the emergence of a regulatory T-cell population that significantly inhibits proliferation, IFN-γ production and CD40L expression among stimulated effector T cells.Conclusions These results reinforce the proposal of using bortezomib in the prevention of graft versus host disease and, moreover, in the generation of regulatory T-cell populations, that could be used in the treatment of multiple T-cell mediated diseases.
PB Ferrata Storti Foundation
SN 0390-6078
YR 2009
FD 2009
LK https://uvadoc.uva.es/handle/10324/55178
UL https://uvadoc.uva.es/handle/10324/55178
LA eng
NO Haematologica, 2009, Vol. 94, Nº. 7, págs. 975-983
NO Producción Científica
DS UVaDOC
RD 11-jul-2024