Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders

Autores
Ouyang, Ying; Juszczynski, Przemyslaw; Rodig, Scott J.; Green, Michael R.; O´ Donnell, Evan; Currie, Treeve; Armant, Myriam; Takeyama, Kunihiko; Monti, Stefano; Rabinovich, Gabriel Adrián; Ritz, Jerome; Kutok, Jeffery L.; Shipp, Margaret A.
Año de publicación
2011
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Posttransplant lymphoproliferative disorders (PTLDs) are potentially fatal, EBVdriven B-cell malignancies that develop in immunocompromised solid organ or hematopoietic stem cell recipients. In PTLD, the expression of EBV proteins, including latent membrane protein 1 (LMP1) and LMP2A, viral immune evasion strategies, and impaired host immune surveillance foster the proliferation of EBV-transformed B cells. Current PTLD treatment strategies include reduction of immunosuppression, which increases the risk of graft rejection, anti-CD20 treatment, combination chemotherapy, and administration of EBV-specific cytotoxic T cells. In the present study, we report that EBV-transformed lymphoblastoid Bcell lines (LCLs) and primary PTLDs overexpress galectin-1 (Gal1), a carbohydratebinding lectin that induces tolerogenic dendritic cells and triggers the selective apoptosis of CD4 Th1 and Th17 cells and cytotoxic T cells. In transcriptional reporter assays, LMP2A and LMP1 each increased Gal1-driven luciferase expression, and the combination of LMP2A and LMP1 was additive. In addition, small interfering RNA (siRNA)–mediated depletion of LMP2A decreased Gal1 protein abundance in EBV-transformed LCLs. Gal1 expression in LCLs was dependent on both activating protein 1 (AP-1) and PI3K. A newly developed neutralizing Gal1 mAb selectively inhibited Gal1-mediated apoptosis of EBV-specific CD8 T cells. Given the tolerogenic and immunosuppressive function of Gal1, antibody-mediated Gal1 neutralization may represent a novel immunotherapeutic strategy for PTLD and other Gal1-expressing tumors.
Fil: Ouyang, Ying. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: Juszczynski, Przemyslaw. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: Rodig, Scott J.. Brigham and Women’s Hospital. Department of Pathology; Estados Unidos
Fil: Green, Michael R.. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: O´ Donnell, Evan. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: Currie, Treeve. Brigham and Women’s Hospital. Department of Pathology; Estados Unidos
Fil: Armant, Myriam. Immune Disease Institute/Harvard Medical School. Center for Human Cell Therapy; Estados Unidos
Fil: Takeyama, Kunihiko. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: Monti, Stefano. Broad Institute; Estados Unidos
Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Ritz, Jerome. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: Kutok, Jeffery L.. Brigham and Women’s Hospital. Department of Pathology; Estados Unidos
Fil: Shipp, Margaret A.. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Materia
Epstein Barr-Virus
Lymphoproliferative Disorders
Galectin-1
Transplantation
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/10661
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/10661
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disordersOuyang, YingJuszczynski, PrzemyslawRodig, Scott J.Green, Michael R.O´ Donnell, EvanCurrie, TreeveArmant, MyriamTakeyama, KunihikoMonti, StefanoRabinovich, Gabriel AdriánRitz, JeromeKutok, Jeffery L.Shipp, Margaret A.Epstein Barr-VirusLymphoproliferative DisordersGalectin-1Transplantationhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Posttransplant lymphoproliferative disorders (PTLDs) are potentially fatal, EBVdriven B-cell malignancies that develop in immunocompromised solid organ or hematopoietic stem cell recipients. In PTLD, the expression of EBV proteins, including latent membrane protein 1 (LMP1) and LMP2A, viral immune evasion strategies, and impaired host immune surveillance foster the proliferation of EBV-transformed B cells. Current PTLD treatment strategies include reduction of immunosuppression, which increases the risk of graft rejection, anti-CD20 treatment, combination chemotherapy, and administration of EBV-specific cytotoxic T cells. In the present study, we report that EBV-transformed lymphoblastoid Bcell lines (LCLs) and primary PTLDs overexpress galectin-1 (Gal1), a carbohydratebinding lectin that induces tolerogenic dendritic cells and triggers the selective apoptosis of CD4 Th1 and Th17 cells and cytotoxic T cells. In transcriptional reporter assays, LMP2A and LMP1 each increased Gal1-driven luciferase expression, and the combination of LMP2A and LMP1 was additive. In addition, small interfering RNA (siRNA)–mediated depletion of LMP2A decreased Gal1 protein abundance in EBV-transformed LCLs. Gal1 expression in LCLs was dependent on both activating protein 1 (AP-1) and PI3K. A newly developed neutralizing Gal1 mAb selectively inhibited Gal1-mediated apoptosis of EBV-specific CD8 T cells. Given the tolerogenic and immunosuppressive function of Gal1, antibody-mediated Gal1 neutralization may represent a novel immunotherapeutic strategy for PTLD and other Gal1-expressing tumors.Fil: Ouyang, Ying. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados UnidosFil: Juszczynski, Przemyslaw. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados UnidosFil: Rodig, Scott J.. Brigham and Women’s Hospital. Department of Pathology; Estados UnidosFil: Green, Michael R.. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados UnidosFil: O´ Donnell, Evan. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados UnidosFil: Currie, Treeve. Brigham and Women’s Hospital. Department of Pathology; Estados UnidosFil: Armant, Myriam. Immune Disease Institute/Harvard Medical School. Center for Human Cell Therapy; Estados UnidosFil: Takeyama, Kunihiko. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados UnidosFil: Monti, Stefano. Broad Institute; Estados UnidosFil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); ArgentinaFil: Ritz, Jerome. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados UnidosFil: Kutok, Jeffery L.. Brigham and Women’s Hospital. Department of Pathology; Estados UnidosFil: Shipp, Margaret A.. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados UnidosAmerican Society Of Hematology2011-06info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/10661Ouyang, Ying; Juszczynski, Przemyslaw; Rodig, Scott J.; Green, Michael R.; O´ Donnell, Evan; et al.; Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders; American Society Of Hematology; Blood, The Journal Of The American Society Of Hematology - Print; 117; 16; 6-2011; 4315-43220006-4971enginfo:eu-repo/semantics/altIdentifier/url/http://www.bloodjournal.org/content/117/16/4315?sso-checked=trueinfo:eu-repo/semantics/altIdentifier/doi/10.1182/blood-2010-11-320481info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-15T14:37:39Zoai:ri.conicet.gov.ar:11336/10661instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-10-15 14:37:40.185CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders
title Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders
spellingShingle Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders
Ouyang, Ying
Epstein Barr-Virus
Lymphoproliferative Disorders
Galectin-1
Transplantation
title_short Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders
title_full Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders
title_fullStr Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders
title_full_unstemmed Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders
title_sort Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders
dc.creator.none.fl_str_mv Ouyang, Ying
Juszczynski, Przemyslaw
Rodig, Scott J.
Green, Michael R.
O´ Donnell, Evan
Currie, Treeve
Armant, Myriam
Takeyama, Kunihiko
Monti, Stefano
Rabinovich, Gabriel Adrián
Ritz, Jerome
Kutok, Jeffery L.
Shipp, Margaret A.
author Ouyang, Ying
author_facet Ouyang, Ying
Juszczynski, Przemyslaw
Rodig, Scott J.
Green, Michael R.
O´ Donnell, Evan
Currie, Treeve
Armant, Myriam
Takeyama, Kunihiko
Monti, Stefano
Rabinovich, Gabriel Adrián
Ritz, Jerome
Kutok, Jeffery L.
Shipp, Margaret A.
author_role author
author2 Juszczynski, Przemyslaw
Rodig, Scott J.
Green, Michael R.
O´ Donnell, Evan
Currie, Treeve
Armant, Myriam
Takeyama, Kunihiko
Monti, Stefano
Rabinovich, Gabriel Adrián
Ritz, Jerome
Kutok, Jeffery L.
Shipp, Margaret A.
author2_role author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Epstein Barr-Virus
Lymphoproliferative Disorders
Galectin-1
Transplantation
topic Epstein Barr-Virus
Lymphoproliferative Disorders
Galectin-1
Transplantation
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Posttransplant lymphoproliferative disorders (PTLDs) are potentially fatal, EBVdriven B-cell malignancies that develop in immunocompromised solid organ or hematopoietic stem cell recipients. In PTLD, the expression of EBV proteins, including latent membrane protein 1 (LMP1) and LMP2A, viral immune evasion strategies, and impaired host immune surveillance foster the proliferation of EBV-transformed B cells. Current PTLD treatment strategies include reduction of immunosuppression, which increases the risk of graft rejection, anti-CD20 treatment, combination chemotherapy, and administration of EBV-specific cytotoxic T cells. In the present study, we report that EBV-transformed lymphoblastoid Bcell lines (LCLs) and primary PTLDs overexpress galectin-1 (Gal1), a carbohydratebinding lectin that induces tolerogenic dendritic cells and triggers the selective apoptosis of CD4 Th1 and Th17 cells and cytotoxic T cells. In transcriptional reporter assays, LMP2A and LMP1 each increased Gal1-driven luciferase expression, and the combination of LMP2A and LMP1 was additive. In addition, small interfering RNA (siRNA)–mediated depletion of LMP2A decreased Gal1 protein abundance in EBV-transformed LCLs. Gal1 expression in LCLs was dependent on both activating protein 1 (AP-1) and PI3K. A newly developed neutralizing Gal1 mAb selectively inhibited Gal1-mediated apoptosis of EBV-specific CD8 T cells. Given the tolerogenic and immunosuppressive function of Gal1, antibody-mediated Gal1 neutralization may represent a novel immunotherapeutic strategy for PTLD and other Gal1-expressing tumors.
Fil: Ouyang, Ying. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: Juszczynski, Przemyslaw. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: Rodig, Scott J.. Brigham and Women’s Hospital. Department of Pathology; Estados Unidos
Fil: Green, Michael R.. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: O´ Donnell, Evan. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: Currie, Treeve. Brigham and Women’s Hospital. Department of Pathology; Estados Unidos
Fil: Armant, Myriam. Immune Disease Institute/Harvard Medical School. Center for Human Cell Therapy; Estados Unidos
Fil: Takeyama, Kunihiko. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: Monti, Stefano. Broad Institute; Estados Unidos
Fil: Rabinovich, Gabriel Adrián. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina
Fil: Ritz, Jerome. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
Fil: Kutok, Jeffery L.. Brigham and Women’s Hospital. Department of Pathology; Estados Unidos
Fil: Shipp, Margaret A.. Dana-Farber Cancer Institute. Department of Medical Oncology; Estados Unidos
description Posttransplant lymphoproliferative disorders (PTLDs) are potentially fatal, EBVdriven B-cell malignancies that develop in immunocompromised solid organ or hematopoietic stem cell recipients. In PTLD, the expression of EBV proteins, including latent membrane protein 1 (LMP1) and LMP2A, viral immune evasion strategies, and impaired host immune surveillance foster the proliferation of EBV-transformed B cells. Current PTLD treatment strategies include reduction of immunosuppression, which increases the risk of graft rejection, anti-CD20 treatment, combination chemotherapy, and administration of EBV-specific cytotoxic T cells. In the present study, we report that EBV-transformed lymphoblastoid Bcell lines (LCLs) and primary PTLDs overexpress galectin-1 (Gal1), a carbohydratebinding lectin that induces tolerogenic dendritic cells and triggers the selective apoptosis of CD4 Th1 and Th17 cells and cytotoxic T cells. In transcriptional reporter assays, LMP2A and LMP1 each increased Gal1-driven luciferase expression, and the combination of LMP2A and LMP1 was additive. In addition, small interfering RNA (siRNA)–mediated depletion of LMP2A decreased Gal1 protein abundance in EBV-transformed LCLs. Gal1 expression in LCLs was dependent on both activating protein 1 (AP-1) and PI3K. A newly developed neutralizing Gal1 mAb selectively inhibited Gal1-mediated apoptosis of EBV-specific CD8 T cells. Given the tolerogenic and immunosuppressive function of Gal1, antibody-mediated Gal1 neutralization may represent a novel immunotherapeutic strategy for PTLD and other Gal1-expressing tumors.
publishDate 2011
dc.date.none.fl_str_mv 2011-06
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/10661
Ouyang, Ying; Juszczynski, Przemyslaw; Rodig, Scott J.; Green, Michael R.; O´ Donnell, Evan; et al.; Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders; American Society Of Hematology; Blood, The Journal Of The American Society Of Hematology - Print; 117; 16; 6-2011; 4315-4322
0006-4971
url http://hdl.handle.net/11336/10661
identifier_str_mv Ouyang, Ying; Juszczynski, Przemyslaw; Rodig, Scott J.; Green, Michael R.; O´ Donnell, Evan; et al.; Viral induction and targeted inhibition of galectin-1 in EBV + posttransplant lymphoproliferative disorders; American Society Of Hematology; Blood, The Journal Of The American Society Of Hematology - Print; 117; 16; 6-2011; 4315-4322
0006-4971
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.bloodjournal.org/content/117/16/4315?sso-checked=true
info:eu-repo/semantics/altIdentifier/doi/10.1182/blood-2010-11-320481
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society Of Hematology
publisher.none.fl_str_mv American Society Of Hematology
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.22299

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