Dual Costimulatory and Coinhibitory Targeting with a Hybrid Fusion Protein as an Immunomodulatory Therapy in Lupus Nephritis Mice Models

Systemic lupus erythematosus is a complex autoimmune disorder mostly mediated by B-cells in which costimulatory signals are involved. This immune dysregulation can cause tissue damage and inflammation of the kidney, resulting in lupus nephritis and chronic renal failure. Given the previous experienc...

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Autores: Guiteras, Jordi, Crespo Fernández, Elena, Fontova, Pere, Bolaños, Nuria, Gomà, Montse, Castaño, Esther, Bestard Matamoros, Oriol, Grinyo Boira, Josep M., Torras Ambròs, Joan
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2022
País:España
Institución:Universidad de Barcelona
Repositorio:Dipòsit Digital de la UB
OAI Identifier:oai:diposit.ub.edu:2445/188927
Acceso en línea:https://hdl.handle.net/2445/188927
Access Level:acceso abierto
Palabra clave:Lupus eritematós
Malalties autoimmunitàries
Malalties del ronyó
Immunoregulació
Lupus erythematosus
Autoimmune diseases
Kidney diseases
Immunoregulation
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spelling Dual Costimulatory and Coinhibitory Targeting with a Hybrid Fusion Protein as an Immunomodulatory Therapy in Lupus Nephritis Mice ModelsGuiteras, JordiCrespo Fernández, ElenaFontova, PereBolaños, NuriaGomà, MontseCastaño, EstherBestard Matamoros, OriolGrinyo Boira, Josep M.Torras Ambròs, JoanLupus eritematósMalalties autoimmunitàriesMalalties del ronyóImmunoregulacióLupus erythematosusAutoimmune diseasesKidney diseasesImmunoregulationSystemic lupus erythematosus is a complex autoimmune disorder mostly mediated by B-cells in which costimulatory signals are involved. This immune dysregulation can cause tissue damage and inflammation of the kidney, resulting in lupus nephritis and chronic renal failure. Given the previous experience reported with CTLA4-Ig as well as recent understanding of the PD-1 pathway in this setting, our group was encouraged to evaluate, in the NZBWF1 model, a human fusion recombinant protein (Hybri) with two domains: CTLA4, blocking the CD28-CD80 costimulatory pathway, and PD-L2, exacerbating the PD-1-PD-L2 coinhibitory pathway. After achieving good results in this model, we decided to validate the therapeutic effect of Hybri in the more severe MRL/lpr model of lupus nephritis. The intraperitoneal administration of Hybri prevented the progression of proteinuria and anti-dsDNA antibodies to levels like those of cyclophosphamide and reduced the histological score, infiltration of B-cells, T-cells, and macrophages and immune deposition in both lupus-prone models. Additionally, Hybri treatment produced changes in both inflammatory-related circulating cytokines and kidney gene expression. To summarize, both in vivo studies revealed that the Hybri effect on costimulatory-coinhibitory pathways may effectively mitigate lupus nephritis, with potential for use as a maintenance therapy.MDPI AG2022info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfhttps://hdl.handle.net/2445/188927Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Dipòsit Digital de la UBinstname:Universidad de BarcelonaInglésReproducció del document publicat a: https://doi.org/10.3390/ijms23158411International Journal of Molecular Sciences, 2022, vol. 23, num. 15, p. 8411https://doi.org/10.3390/ijms23158411cc by (c) Guiteras, Jordi et al., 2022http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:diposit.ub.edu:2445/1889272026-05-27T06:46:51Z
dc.title.none.fl_str_mv Dual Costimulatory and Coinhibitory Targeting with a Hybrid Fusion Protein as an Immunomodulatory Therapy in Lupus Nephritis Mice Models
title Dual Costimulatory and Coinhibitory Targeting with a Hybrid Fusion Protein as an Immunomodulatory Therapy in Lupus Nephritis Mice Models
spellingShingle Dual Costimulatory and Coinhibitory Targeting with a Hybrid Fusion Protein as an Immunomodulatory Therapy in Lupus Nephritis Mice Models
Guiteras, Jordi
Lupus eritematós
Malalties autoimmunitàries
Malalties del ronyó
Immunoregulació
Lupus erythematosus
Autoimmune diseases
Kidney diseases
Immunoregulation
title_short Dual Costimulatory and Coinhibitory Targeting with a Hybrid Fusion Protein as an Immunomodulatory Therapy in Lupus Nephritis Mice Models
title_full Dual Costimulatory and Coinhibitory Targeting with a Hybrid Fusion Protein as an Immunomodulatory Therapy in Lupus Nephritis Mice Models
title_fullStr Dual Costimulatory and Coinhibitory Targeting with a Hybrid Fusion Protein as an Immunomodulatory Therapy in Lupus Nephritis Mice Models
title_full_unstemmed Dual Costimulatory and Coinhibitory Targeting with a Hybrid Fusion Protein as an Immunomodulatory Therapy in Lupus Nephritis Mice Models
title_sort Dual Costimulatory and Coinhibitory Targeting with a Hybrid Fusion Protein as an Immunomodulatory Therapy in Lupus Nephritis Mice Models
dc.creator.none.fl_str_mv Guiteras, Jordi
Crespo Fernández, Elena
Fontova, Pere
Bolaños, Nuria
Gomà, Montse
Castaño, Esther
Bestard Matamoros, Oriol
Grinyo Boira, Josep M.
Torras Ambròs, Joan
author Guiteras, Jordi
author_facet Guiteras, Jordi
Crespo Fernández, Elena
Fontova, Pere
Bolaños, Nuria
Gomà, Montse
Castaño, Esther
Bestard Matamoros, Oriol
Grinyo Boira, Josep M.
Torras Ambròs, Joan
author_role author
author2 Crespo Fernández, Elena
Fontova, Pere
Bolaños, Nuria
Gomà, Montse
Castaño, Esther
Bestard Matamoros, Oriol
Grinyo Boira, Josep M.
Torras Ambròs, Joan
author2_role author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Lupus eritematós
Malalties autoimmunitàries
Malalties del ronyó
Immunoregulació
Lupus erythematosus
Autoimmune diseases
Kidney diseases
Immunoregulation
topic Lupus eritematós
Malalties autoimmunitàries
Malalties del ronyó
Immunoregulació
Lupus erythematosus
Autoimmune diseases
Kidney diseases
Immunoregulation
description Systemic lupus erythematosus is a complex autoimmune disorder mostly mediated by B-cells in which costimulatory signals are involved. This immune dysregulation can cause tissue damage and inflammation of the kidney, resulting in lupus nephritis and chronic renal failure. Given the previous experience reported with CTLA4-Ig as well as recent understanding of the PD-1 pathway in this setting, our group was encouraged to evaluate, in the NZBWF1 model, a human fusion recombinant protein (Hybri) with two domains: CTLA4, blocking the CD28-CD80 costimulatory pathway, and PD-L2, exacerbating the PD-1-PD-L2 coinhibitory pathway. After achieving good results in this model, we decided to validate the therapeutic effect of Hybri in the more severe MRL/lpr model of lupus nephritis. The intraperitoneal administration of Hybri prevented the progression of proteinuria and anti-dsDNA antibodies to levels like those of cyclophosphamide and reduced the histological score, infiltration of B-cells, T-cells, and macrophages and immune deposition in both lupus-prone models. Additionally, Hybri treatment produced changes in both inflammatory-related circulating cytokines and kidney gene expression. To summarize, both in vivo studies revealed that the Hybri effect on costimulatory-coinhibitory pathways may effectively mitigate lupus nephritis, with potential for use as a maintenance therapy.
publishDate 2022
dc.date.none.fl_str_mv 2022
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/188927
url https://hdl.handle.net/2445/188927
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.3390/ijms23158411
International Journal of Molecular Sciences, 2022, vol. 23, num. 15, p. 8411
https://doi.org/10.3390/ijms23158411
dc.rights.none.fl_str_mv cc by (c) Guiteras, Jordi et al., 2022
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Guiteras, Jordi et al., 2022
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv MDPI AG
publisher.none.fl_str_mv MDPI AG
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
reponame:Dipòsit Digital de la UB
instname:Universidad de Barcelona
instname_str Universidad de Barcelona
reponame_str Dipòsit Digital de la UB
collection Dipòsit Digital de la UB
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,301603

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