title: Effect of mTORC1/mTORC2 inhibition on T cell function: potential role in graft-versus-host disease control.
abstract: The mechanistic target of rapamycin (mTOR) pathway is crucial for the activation and function of T cells, which play an essential role in the development of graft-versus-host disease (GvHD). Despite its partial ability to block mTOR pathway, the mTORC1 inhibitor rapamycin has shown encouraging results in the control of GvHD. Therefore, we considered that simultaneous targeting of both mTORC1 and mTORC2 complexes could exert a more potent inhibition of T cell activation and, thus, could have utility in GvHD control. To assess this assumption, we have used the dual mTORC1/mTORC2 inhibitors CC214-1 and CC214-2. In vitro studies confirmed the superior ability of CC214-1 versus rapamycin to block mTORC1 and mTORC2 activity and to reduce T cell proliferation. Both drugs induced a similar decrease in Th1/Th2 cytokine secretion, but CC214-1 was more efficient in inhibiting naïve T cell activation and the expression of T-cell activation markers. In addition, CC214-1 induced specific tolerance against alloantigens, while preserving anti-cytomegalovirus response. Finally, in a mouse model of GvHD, the administration of CC214-2 significantly improved mice survival and decreased GvHD-induced damages. In conclusion, the current study shows, for the first time, the immunosuppressive ability of CC214-1 on T lymphocytes and illustrates the role of CC214-2 in the allogeneic transplantation setting as a possible GvHD prophylaxis agent.
authors.affiliation: Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.|Centro de Investigación del Cáncer, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Ma Carmen
authors.initials: MC
authors.lastname: Herrero-Sánchez
authors.affiliation: Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.|Centro de Investigación del Cáncer, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Rodríguez-Serrano
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.|Servicio de Citometría, Centro de Investigación del Cáncer, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Julia
authors.initials: J
authors.lastname: Almeida
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.|Centro de Investigación del Cáncer, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: San-Segundo
authors.affiliation: Laboratorio de Inmunoterapia, Clínica Universidad de Navarra, Pamplona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Inogés
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.|Departamento de Patología, Hospital Universitario de Salamanca, Salamanca, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Santos-Briz
authors.affiliation: Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.|Departamento de Biología Celular y Patología, Facultad de Medicina, Salamanca, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: García-Briñón
authors.affiliation: Clínica Universidad de Navarra, Centro de Investigación Médica Aplicada, Instituto de Investigación Sanitaria de Navarra, Pamplona, Spain.
authors.forename: Jesús F
authors.initials: JF
authors.lastname: SanMiguel
authors.affiliation: Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.|Centro de Investigación del Cáncer, Universidad de Salamanca, Salamanca, Spain.
authors.forename: Consuelo
authors.initials: C
authors.lastname: Del Cañizo
authors.affiliation: Servicio de Hematología, Hospital Universitario de Salamanca, Salamanca, Spain.|Instituto de Investigación Biomédica de Salamanca (IBSAL), Salamanca, Spain.
authors.forename: Belén
authors.initials: B
authors.lastname: Blanco
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy / Q000517:prevention & control*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use; D007108:Immune Tolerance / Q000187:drug effects; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors*; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: C588406:6-(4-(1H-1,2,4-triazol-3-yl)phenyl)-1-(2-(tetrahydro-2H-pyran-4-yl)ethyl)-1H-imidazo(4,5-b)pyrazin-2(3H)-one; C583190:CC214-2; D007093:Imidazoles; D046912:Multiprotein Complexes; D011719:Pyrazines; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases
keywords: T cell; graft versus host disease; mTOR inhibitors