title: Targeting of PI3K/AKT/mTOR pathway to inhibit T cell activation and prevent graft-versus-host disease development.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Servicio de Hematología, Hospital Universitario de Salamanca, Paseo de San Vicente 58-182, 37007, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo de San Vicente 58-182, 37007, Salamanca, Spain.|Centro de Investigación del Cáncer, Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
authors.forename: Mª Carmen
authors.initials: MC
authors.lastname: Herrero-Sánchez
authors.affiliation: Servicio de Hematología, Hospital Universitario de Salamanca, Paseo de San Vicente 58-182, 37007, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo de San Vicente 58-182, 37007, Salamanca, Spain.|Centro de Investigación del Cáncer, Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Rodríguez-Serrano
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo de San Vicente 58-182, 37007, Salamanca, Spain.|Centro de Investigación del Cáncer, Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain.|Servicio de Citometría, Centro de Investigación del Cáncer, Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Almeida
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo de San Vicente 58-182, 37007, Salamanca, Spain.|Centro de Investigación del Cáncer, Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: San Segundo
authors.affiliation: Laboratorio de Inmunoterapia, Clínica Universidad de Navarra, Avda. Pío XII 55, 31008, Pamplona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Inogés
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo de San Vicente 58-182, 37007, Salamanca, Spain.|Departamento de Patología, Hospital Universitario de Salamanca, Paseo de San Vicente 58-182, 37007, Salamanca, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Santos-Briz
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo de San Vicente 58-182, 37007, Salamanca, Spain.|Departamento de Biología Celular y Patología, Facultad de Medicina, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: García-Briñón
authors.affiliation: Servicio de Hematología, Hospital Universitario de Salamanca, Paseo de San Vicente 58-182, 37007, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo de San Vicente 58-182, 37007, Salamanca, Spain.|Centro de Investigación del Cáncer, Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
authors.forename: Luis Antonio
authors.initials: LA
authors.lastname: Corchete
authors.affiliation: Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Avda. Pío XII 55, 31008, Pamplona, Spain.
authors.forename: Jesús F
authors.initials: JF
authors.lastname: San Miguel
authors.affiliation: Servicio de Hematología, Hospital Universitario de Salamanca, Paseo de San Vicente 58-182, 37007, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo de San Vicente 58-182, 37007, Salamanca, Spain.|Centro de Investigación del Cáncer, Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Del Cañizo
authors.affiliation: Servicio de Hematología, Hospital Universitario de Salamanca, Paseo de San Vicente 58-182, 37007, Salamanca, Spain. belen_blancod@yahoo.es.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Paseo de San Vicente 58-182, 37007, Salamanca, Spain. belen_blancod@yahoo.es.|Centro de Investigación del Cáncer, Universidad de Salamanca, Campus Miguel de Unamuno, 37007, Salamanca, Spain. belen_blancod@yahoo.es.
authors.forename: Belén
authors.initials: B
authors.lastname: Blanco
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D049109:Cell Proliferation / Q000187:drug effects; D006086:Graft vs Host Disease / Q000517:prevention & control*; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects*; D051379:Mice; D009025:Morpholines / Q000494:pharmacology / Q000627:therapeutic use; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011804:Quinolines / Q000494:pharmacology / Q000627:therapeutic use; D015398:Signal Transduction / Q000187:drug effects; D013601:T-Lymphocytes / Q000276:immunology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D000631:Aminopyridines; D007093:Imidazoles; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C571178:NVP-BKM120; C546842:MTOR protein, human; C531198:dactolisib
keywords: Graft-versus-host disease; Hematopoietic stem cell transplantation; PI3K inhibitor; PI3K/AKT/mTOR pathway; T cell