LAG3 regulates antibody responses in a murine model of kidney transplantation

Autores
Nicosia, Michael; Fan, Ran; Lee, Juyeun; All, Gabriella L.; Gorbacheva, Victoria; Valenzuela, José Ignacio; Yamamoto, Yosuke; Beavers, Ashley; Dvorina, Nina; Baldwin III, William M.; Chuluyan, Hector Eduardo; Araki, Motoo; Gaudette, Brian T.; Fairchild, Robert L.; Min, Booki; Valujskikh, Anna
Año de publicación
2025
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Lymphocyte activation gene-3 (LAG3) is a coinhibitory receptor expressed by various immune cells. While immunomodulatory potential of LAG3 is being explored in cancer and autoimmunity, there is no information on its role following organ transplantation. Our study investigated the functions of LAG3 in a mouse model of renal allograft rejection. LAG3-/- recipients rapidly reject MHC-mismatched renal allografts that are spontaneously accepted by WT recipients, with graft histology characteristic of antibody mediated rejection (ABMR). Depletion of recipient B cells but not CD8+ T cells significantly extended kidney allograft survival in LAG3-/- recipients. Treatment of WT recipients with an antagonistic LAG3 antibody enhanced anti-donor immune responses and induced kidney damage associated with chronic rejection. The studies of conditional LAG3-/- recipients and mixed bone marrow chimeras demonstrated that LAG3 expression on either T or B cells is sufficient to regulate anti-donor humoral immunity but not to induce acute allograft rejection. The numbers and proinflammatory functions of graft-infiltrating NK cells were markedly increased in LAG3-/- recipients suggesting that LAG3 also regulates the effector stage of ABMR. These results are the first to identify LAG3 as a regulator of immune responses to kidney allografts and a potential therapeutic target for ABMR prevention and treatment.
Fil: Nicosia, Michael. No especifíca;
Fil: Fan, Ran. No especifíca;
Fil: Lee, Juyeun. No especifíca;
Fil: All, Gabriella L.. No especifíca;
Fil: Gorbacheva, Victoria. No especifíca;
Fil: Valenzuela, José Ignacio. No especifíca;
Fil: Yamamoto, Yosuke. No especifíca;
Fil: Beavers, Ashley. No especifíca;
Fil: Dvorina, Nina. No especifíca;
Fil: Baldwin III, William M.. No especifíca;
Fil: Chuluyan, Hector Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Araki, Motoo. Okayama University; Japón
Fil: Gaudette, Brian T.. No especifíca;
Fil: Fairchild, Robert L.. No especifíca;
Fil: Min, Booki. No especifíca;
Fil: Valujskikh, Anna. No especifíca;
Materia
LAG3
TRANSPLANTATION
ANTIBODY MEDIATED REJECTION
KIDNEY
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:11336/291385
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/291385
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling LAG3 regulates antibody responses in a murine model of kidney transplantationNicosia, MichaelFan, RanLee, JuyeunAll, Gabriella L.Gorbacheva, VictoriaValenzuela, José IgnacioYamamoto, YosukeBeavers, AshleyDvorina, NinaBaldwin III, William M.Chuluyan, Hector EduardoAraki, MotooGaudette, Brian T.Fairchild, Robert L.Min, BookiValujskikh, AnnaLAG3TRANSPLANTATIONANTIBODY MEDIATED REJECTIONKIDNEYhttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Lymphocyte activation gene-3 (LAG3) is a coinhibitory receptor expressed by various immune cells. While immunomodulatory potential of LAG3 is being explored in cancer and autoimmunity, there is no information on its role following organ transplantation. Our study investigated the functions of LAG3 in a mouse model of renal allograft rejection. LAG3-/- recipients rapidly reject MHC-mismatched renal allografts that are spontaneously accepted by WT recipients, with graft histology characteristic of antibody mediated rejection (ABMR). Depletion of recipient B cells but not CD8+ T cells significantly extended kidney allograft survival in LAG3-/- recipients. Treatment of WT recipients with an antagonistic LAG3 antibody enhanced anti-donor immune responses and induced kidney damage associated with chronic rejection. The studies of conditional LAG3-/- recipients and mixed bone marrow chimeras demonstrated that LAG3 expression on either T or B cells is sufficient to regulate anti-donor humoral immunity but not to induce acute allograft rejection. The numbers and proinflammatory functions of graft-infiltrating NK cells were markedly increased in LAG3-/- recipients suggesting that LAG3 also regulates the effector stage of ABMR. These results are the first to identify LAG3 as a regulator of immune responses to kidney allografts and a potential therapeutic target for ABMR prevention and treatment.Fil: Nicosia, Michael. No especifíca;Fil: Fan, Ran. No especifíca;Fil: Lee, Juyeun. No especifíca;Fil: All, Gabriella L.. No especifíca;Fil: Gorbacheva, Victoria. No especifíca;Fil: Valenzuela, José Ignacio. No especifíca;Fil: Yamamoto, Yosuke. No especifíca;Fil: Beavers, Ashley. No especifíca;Fil: Dvorina, Nina. No especifíca;Fil: Baldwin III, William M.. No especifíca;Fil: Chuluyan, Hector Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Araki, Motoo. Okayama University; JapónFil: Gaudette, Brian T.. No especifíca;Fil: Fairchild, Robert L.. No especifíca;Fil: Min, Booki. No especifíca;Fil: Valujskikh, Anna. No especifíca;American Society for Clinical Investigation2025-05info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/291385Nicosia, Michael; Fan, Ran; Lee, Juyeun; All, Gabriella L.; Gorbacheva, Victoria; et al.; LAG3 regulates antibody responses in a murine model of kidney transplantation; American Society for Clinical Investigation; Journal of Clinical Investigation; 135; 13; 5-2025; 1-181558-8238CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/http://www.jci.org/articles/view/172988info:eu-repo/semantics/altIdentifier/doi/10.1172/JCI172988info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2026-08-25T14:30:54Zoai:ri.conicet.gov.ar:11336/291385instacron: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:34982026-08-25 14:30:54.854CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv LAG3 regulates antibody responses in a murine model of kidney transplantation
title LAG3 regulates antibody responses in a murine model of kidney transplantation
spellingShingle LAG3 regulates antibody responses in a murine model of kidney transplantation
Nicosia, Michael
LAG3
TRANSPLANTATION
ANTIBODY MEDIATED REJECTION
KIDNEY
title_short LAG3 regulates antibody responses in a murine model of kidney transplantation
title_full LAG3 regulates antibody responses in a murine model of kidney transplantation
title_fullStr LAG3 regulates antibody responses in a murine model of kidney transplantation
title_full_unstemmed LAG3 regulates antibody responses in a murine model of kidney transplantation
title_sort LAG3 regulates antibody responses in a murine model of kidney transplantation
dc.creator.none.fl_str_mv Nicosia, Michael
Fan, Ran
Lee, Juyeun
All, Gabriella L.
Gorbacheva, Victoria
Valenzuela, José Ignacio
Yamamoto, Yosuke
Beavers, Ashley
Dvorina, Nina
Baldwin III, William M.
Chuluyan, Hector Eduardo
Araki, Motoo
Gaudette, Brian T.
Fairchild, Robert L.
Min, Booki
Valujskikh, Anna
author Nicosia, Michael
author_facet Nicosia, Michael
Fan, Ran
Lee, Juyeun
All, Gabriella L.
Gorbacheva, Victoria
Valenzuela, José Ignacio
Yamamoto, Yosuke
Beavers, Ashley
Dvorina, Nina
Baldwin III, William M.
Chuluyan, Hector Eduardo
Araki, Motoo
Gaudette, Brian T.
Fairchild, Robert L.
Min, Booki
Valujskikh, Anna
author_role author
author2 Fan, Ran
Lee, Juyeun
All, Gabriella L.
Gorbacheva, Victoria
Valenzuela, José Ignacio
Yamamoto, Yosuke
Beavers, Ashley
Dvorina, Nina
Baldwin III, William M.
Chuluyan, Hector Eduardo
Araki, Motoo
Gaudette, Brian T.
Fairchild, Robert L.
Min, Booki
Valujskikh, Anna
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv LAG3
TRANSPLANTATION
ANTIBODY MEDIATED REJECTION
KIDNEY
topic LAG3
TRANSPLANTATION
ANTIBODY MEDIATED REJECTION
KIDNEY
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Lymphocyte activation gene-3 (LAG3) is a coinhibitory receptor expressed by various immune cells. While immunomodulatory potential of LAG3 is being explored in cancer and autoimmunity, there is no information on its role following organ transplantation. Our study investigated the functions of LAG3 in a mouse model of renal allograft rejection. LAG3-/- recipients rapidly reject MHC-mismatched renal allografts that are spontaneously accepted by WT recipients, with graft histology characteristic of antibody mediated rejection (ABMR). Depletion of recipient B cells but not CD8+ T cells significantly extended kidney allograft survival in LAG3-/- recipients. Treatment of WT recipients with an antagonistic LAG3 antibody enhanced anti-donor immune responses and induced kidney damage associated with chronic rejection. The studies of conditional LAG3-/- recipients and mixed bone marrow chimeras demonstrated that LAG3 expression on either T or B cells is sufficient to regulate anti-donor humoral immunity but not to induce acute allograft rejection. The numbers and proinflammatory functions of graft-infiltrating NK cells were markedly increased in LAG3-/- recipients suggesting that LAG3 also regulates the effector stage of ABMR. These results are the first to identify LAG3 as a regulator of immune responses to kidney allografts and a potential therapeutic target for ABMR prevention and treatment.
Fil: Nicosia, Michael. No especifíca;
Fil: Fan, Ran. No especifíca;
Fil: Lee, Juyeun. No especifíca;
Fil: All, Gabriella L.. No especifíca;
Fil: Gorbacheva, Victoria. No especifíca;
Fil: Valenzuela, José Ignacio. No especifíca;
Fil: Yamamoto, Yosuke. No especifíca;
Fil: Beavers, Ashley. No especifíca;
Fil: Dvorina, Nina. No especifíca;
Fil: Baldwin III, William M.. No especifíca;
Fil: Chuluyan, Hector Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina
Fil: Araki, Motoo. Okayama University; Japón
Fil: Gaudette, Brian T.. No especifíca;
Fil: Fairchild, Robert L.. No especifíca;
Fil: Min, Booki. No especifíca;
Fil: Valujskikh, Anna. No especifíca;
description Lymphocyte activation gene-3 (LAG3) is a coinhibitory receptor expressed by various immune cells. While immunomodulatory potential of LAG3 is being explored in cancer and autoimmunity, there is no information on its role following organ transplantation. Our study investigated the functions of LAG3 in a mouse model of renal allograft rejection. LAG3-/- recipients rapidly reject MHC-mismatched renal allografts that are spontaneously accepted by WT recipients, with graft histology characteristic of antibody mediated rejection (ABMR). Depletion of recipient B cells but not CD8+ T cells significantly extended kidney allograft survival in LAG3-/- recipients. Treatment of WT recipients with an antagonistic LAG3 antibody enhanced anti-donor immune responses and induced kidney damage associated with chronic rejection. The studies of conditional LAG3-/- recipients and mixed bone marrow chimeras demonstrated that LAG3 expression on either T or B cells is sufficient to regulate anti-donor humoral immunity but not to induce acute allograft rejection. The numbers and proinflammatory functions of graft-infiltrating NK cells were markedly increased in LAG3-/- recipients suggesting that LAG3 also regulates the effector stage of ABMR. These results are the first to identify LAG3 as a regulator of immune responses to kidney allografts and a potential therapeutic target for ABMR prevention and treatment.
publishDate 2025
dc.date.none.fl_str_mv 2025-05
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/11336/291385
Nicosia, Michael; Fan, Ran; Lee, Juyeun; All, Gabriella L.; Gorbacheva, Victoria; et al.; LAG3 regulates antibody responses in a murine model of kidney transplantation; American Society for Clinical Investigation; Journal of Clinical Investigation; 135; 13; 5-2025; 1-18
1558-8238
CONICET Digital
CONICET
url http://hdl.handle.net/11336/291385
identifier_str_mv Nicosia, Michael; Fan, Ran; Lee, Juyeun; All, Gabriella L.; Gorbacheva, Victoria; et al.; LAG3 regulates antibody responses in a murine model of kidney transplantation; American Society for Clinical Investigation; Journal of Clinical Investigation; 135; 13; 5-2025; 1-18
1558-8238
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/http://www.jci.org/articles/view/172988
info:eu-repo/semantics/altIdentifier/doi/10.1172/JCI172988
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 for Clinical Investigation
publisher.none.fl_str_mv American Society for Clinical Investigation
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 13.265058

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