Human neutrophil elastase proteolytic activity in Ulcerative colitis favors the loss of function of therapeutic monoclonal antibodies

Autores
Curciarello, Renata; Sobande, Toni; Jones, Samantha; Giuffrida, Paolo; Di Sabatino, Antonio; Docena, Guillermo H.; Macdonald, Thomas T.; Klaartje, Kok
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
Purpose: Proteases play an essential role in the pathophysiology of inflammatory bowel disease (IBD), contributing to the intestinal mucosal lesions through the degradation of the extracellular matrix and alteration of the barrier function. Ulcerative colitis (UC) is characterized by an extensive infiltrate of neutrophils into the mucosa and hence, increased proteolytic activity. Human neutrophil elastase (HNE) is a serine protease that has been reported to be increased in UC patients’ intestinal mucosa. Based on our previous studies, we hypothesized that HNE might induce proteolytic degradation and loss of function of therapeutic monoclonal antibodies in IBD patients. Patients and Methods: Elastase expression and elastinolytic activity were determined in mucosal explants from ulcerative colitis patients (n=6) and cultured ex vivo in the presence or absence of recombinant elafin. Enzymatic digestions of therapeutic monoclonal antibodies were performed using recombinant HNE and elafin. The integrity of the therapeutic antibodies was evaluated by immunoblotting and protein G binding assay, whereas their TNFneutralizing activity was assessed with a reporter cell line. Results: We found that HNE and its elastinolytic activity were increased in the gut mucosa of UC patients. We also demonstrated that HNE cleaved biological drugs, impairing the TNF-α neutralizing capacity of anti-TNF monoclonal antibodies. This proteolytic degradation was inhibited by the addition of the specific inhibitor, elafin. Conclusion: Our results suggest that the high level of proteolytic degradation by mucosal neutrophil elastase, along with a potential imbalance with elafin, contributes to the loss of function of biologic agents, which are currently used in patients with IBD. These findings might explain the non-responsiveness of UC patients to therapeutic monoclonal antibodies and suggest the potential beneficial concomitant use of elafin in this treatment.
Fil: Curciarello, Renata. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; Argentina. University of London; Reino Unido
Fil: Sobande, Toni. University of London; Reino Unido
Fil: Jones, Samantha. University of London; Reino Unido
Fil: Giuffrida, Paolo. University of London; Reino Unido. Universita Degli Studi Di Pavia; Italia
Fil: Di Sabatino, Antonio. Universita Degli Studi Di Pavia; Italia
Fil: Docena, Guillermo H.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; Argentina
Fil: Macdonald, Thomas T.. University of London; Reino Unido
Fil: Klaartje, Kok. University of London; Reino Unido. Royal London Hospital; Reino Unido
Materia
ELASTINOLYTIC ACTIVITY
ELAFIN
ANTI-TNF
INFLAMMATORY BOWEL DISEASE
BIOLOGICAL DRUGS
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/154829
Acceder
id CONICETDig_f0a6c1730e35979685ebe8a50f60e00e
oai_identifier_str oai:ri.conicet.gov.ar:11336/154829
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling Human neutrophil elastase proteolytic activity in Ulcerative colitis favors the loss of function of therapeutic monoclonal antibodiesCurciarello, RenataSobande, ToniJones, SamanthaGiuffrida, PaoloDi Sabatino, AntonioDocena, Guillermo H.Macdonald, Thomas T.Klaartje, KokELASTINOLYTIC ACTIVITYELAFINANTI-TNFINFLAMMATORY BOWEL DISEASEBIOLOGICAL DRUGShttps://purl.org/becyt/ford/3.1https://purl.org/becyt/ford/3Purpose: Proteases play an essential role in the pathophysiology of inflammatory bowel disease (IBD), contributing to the intestinal mucosal lesions through the degradation of the extracellular matrix and alteration of the barrier function. Ulcerative colitis (UC) is characterized by an extensive infiltrate of neutrophils into the mucosa and hence, increased proteolytic activity. Human neutrophil elastase (HNE) is a serine protease that has been reported to be increased in UC patients’ intestinal mucosa. Based on our previous studies, we hypothesized that HNE might induce proteolytic degradation and loss of function of therapeutic monoclonal antibodies in IBD patients. Patients and Methods: Elastase expression and elastinolytic activity were determined in mucosal explants from ulcerative colitis patients (n=6) and cultured ex vivo in the presence or absence of recombinant elafin. Enzymatic digestions of therapeutic monoclonal antibodies were performed using recombinant HNE and elafin. The integrity of the therapeutic antibodies was evaluated by immunoblotting and protein G binding assay, whereas their TNFneutralizing activity was assessed with a reporter cell line. Results: We found that HNE and its elastinolytic activity were increased in the gut mucosa of UC patients. We also demonstrated that HNE cleaved biological drugs, impairing the TNF-α neutralizing capacity of anti-TNF monoclonal antibodies. This proteolytic degradation was inhibited by the addition of the specific inhibitor, elafin. Conclusion: Our results suggest that the high level of proteolytic degradation by mucosal neutrophil elastase, along with a potential imbalance with elafin, contributes to the loss of function of biologic agents, which are currently used in patients with IBD. These findings might explain the non-responsiveness of UC patients to therapeutic monoclonal antibodies and suggest the potential beneficial concomitant use of elafin in this treatment.Fil: Curciarello, Renata. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; Argentina. University of London; Reino UnidoFil: Sobande, Toni. University of London; Reino UnidoFil: Jones, Samantha. University of London; Reino UnidoFil: Giuffrida, Paolo. University of London; Reino Unido. Universita Degli Studi Di Pavia; ItaliaFil: Di Sabatino, Antonio. Universita Degli Studi Di Pavia; ItaliaFil: Docena, Guillermo H.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; ArgentinaFil: Macdonald, Thomas T.. University of London; Reino UnidoFil: Klaartje, Kok. University of London; Reino Unido. Royal London Hospital; Reino UnidoDove Press2020-05-22info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/154829Curciarello, Renata; Sobande, Toni; Jones, Samantha; Giuffrida, Paolo; Di Sabatino, Antonio; et al.; Human neutrophil elastase proteolytic activity in Ulcerative colitis favors the loss of function of therapeutic monoclonal antibodies; Dove Press; Journal of Inflammation Research; 13; 22-5-2020; 233-2431178-7031CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/url/https://www.dovepress.com/articles.php?article_id=54030info:eu-repo/semantics/altIdentifier/doi/10.2147/JIR.S234710info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-10-22T11:10:55Zoai:ri.conicet.gov.ar:11336/154829instacron: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:34982025-10-22 11:10:55.797CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv Human neutrophil elastase proteolytic activity in Ulcerative colitis favors the loss of function of therapeutic monoclonal antibodies
title Human neutrophil elastase proteolytic activity in Ulcerative colitis favors the loss of function of therapeutic monoclonal antibodies
spellingShingle Human neutrophil elastase proteolytic activity in Ulcerative colitis favors the loss of function of therapeutic monoclonal antibodies
Curciarello, Renata
ELASTINOLYTIC ACTIVITY
ELAFIN
ANTI-TNF
INFLAMMATORY BOWEL DISEASE
BIOLOGICAL DRUGS
title_short Human neutrophil elastase proteolytic activity in Ulcerative colitis favors the loss of function of therapeutic monoclonal antibodies
title_full Human neutrophil elastase proteolytic activity in Ulcerative colitis favors the loss of function of therapeutic monoclonal antibodies
title_fullStr Human neutrophil elastase proteolytic activity in Ulcerative colitis favors the loss of function of therapeutic monoclonal antibodies
title_full_unstemmed Human neutrophil elastase proteolytic activity in Ulcerative colitis favors the loss of function of therapeutic monoclonal antibodies
title_sort Human neutrophil elastase proteolytic activity in Ulcerative colitis favors the loss of function of therapeutic monoclonal antibodies
dc.creator.none.fl_str_mv Curciarello, Renata
Sobande, Toni
Jones, Samantha
Giuffrida, Paolo
Di Sabatino, Antonio
Docena, Guillermo H.
Macdonald, Thomas T.
Klaartje, Kok
author Curciarello, Renata
author_facet Curciarello, Renata
Sobande, Toni
Jones, Samantha
Giuffrida, Paolo
Di Sabatino, Antonio
Docena, Guillermo H.
Macdonald, Thomas T.
Klaartje, Kok
author_role author
author2 Sobande, Toni
Jones, Samantha
Giuffrida, Paolo
Di Sabatino, Antonio
Docena, Guillermo H.
Macdonald, Thomas T.
Klaartje, Kok
author2_role author
author
author
author
author
author
author
dc.subject.none.fl_str_mv ELASTINOLYTIC ACTIVITY
ELAFIN
ANTI-TNF
INFLAMMATORY BOWEL DISEASE
BIOLOGICAL DRUGS
topic ELASTINOLYTIC ACTIVITY
ELAFIN
ANTI-TNF
INFLAMMATORY BOWEL DISEASE
BIOLOGICAL DRUGS
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.1
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv Purpose: Proteases play an essential role in the pathophysiology of inflammatory bowel disease (IBD), contributing to the intestinal mucosal lesions through the degradation of the extracellular matrix and alteration of the barrier function. Ulcerative colitis (UC) is characterized by an extensive infiltrate of neutrophils into the mucosa and hence, increased proteolytic activity. Human neutrophil elastase (HNE) is a serine protease that has been reported to be increased in UC patients’ intestinal mucosa. Based on our previous studies, we hypothesized that HNE might induce proteolytic degradation and loss of function of therapeutic monoclonal antibodies in IBD patients. Patients and Methods: Elastase expression and elastinolytic activity were determined in mucosal explants from ulcerative colitis patients (n=6) and cultured ex vivo in the presence or absence of recombinant elafin. Enzymatic digestions of therapeutic monoclonal antibodies were performed using recombinant HNE and elafin. The integrity of the therapeutic antibodies was evaluated by immunoblotting and protein G binding assay, whereas their TNFneutralizing activity was assessed with a reporter cell line. Results: We found that HNE and its elastinolytic activity were increased in the gut mucosa of UC patients. We also demonstrated that HNE cleaved biological drugs, impairing the TNF-α neutralizing capacity of anti-TNF monoclonal antibodies. This proteolytic degradation was inhibited by the addition of the specific inhibitor, elafin. Conclusion: Our results suggest that the high level of proteolytic degradation by mucosal neutrophil elastase, along with a potential imbalance with elafin, contributes to the loss of function of biologic agents, which are currently used in patients with IBD. These findings might explain the non-responsiveness of UC patients to therapeutic monoclonal antibodies and suggest the potential beneficial concomitant use of elafin in this treatment.
Fil: Curciarello, Renata. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; Argentina. University of London; Reino Unido
Fil: Sobande, Toni. University of London; Reino Unido
Fil: Jones, Samantha. University of London; Reino Unido
Fil: Giuffrida, Paolo. University of London; Reino Unido. Universita Degli Studi Di Pavia; Italia
Fil: Di Sabatino, Antonio. Universita Degli Studi Di Pavia; Italia
Fil: Docena, Guillermo H.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Estudios Inmunológicos y Fisiopatológicos. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Estudios Inmunológicos y Fisiopatológicos; Argentina
Fil: Macdonald, Thomas T.. University of London; Reino Unido
Fil: Klaartje, Kok. University of London; Reino Unido. Royal London Hospital; Reino Unido
description Purpose: Proteases play an essential role in the pathophysiology of inflammatory bowel disease (IBD), contributing to the intestinal mucosal lesions through the degradation of the extracellular matrix and alteration of the barrier function. Ulcerative colitis (UC) is characterized by an extensive infiltrate of neutrophils into the mucosa and hence, increased proteolytic activity. Human neutrophil elastase (HNE) is a serine protease that has been reported to be increased in UC patients’ intestinal mucosa. Based on our previous studies, we hypothesized that HNE might induce proteolytic degradation and loss of function of therapeutic monoclonal antibodies in IBD patients. Patients and Methods: Elastase expression and elastinolytic activity were determined in mucosal explants from ulcerative colitis patients (n=6) and cultured ex vivo in the presence or absence of recombinant elafin. Enzymatic digestions of therapeutic monoclonal antibodies were performed using recombinant HNE and elafin. The integrity of the therapeutic antibodies was evaluated by immunoblotting and protein G binding assay, whereas their TNFneutralizing activity was assessed with a reporter cell line. Results: We found that HNE and its elastinolytic activity were increased in the gut mucosa of UC patients. We also demonstrated that HNE cleaved biological drugs, impairing the TNF-α neutralizing capacity of anti-TNF monoclonal antibodies. This proteolytic degradation was inhibited by the addition of the specific inhibitor, elafin. Conclusion: Our results suggest that the high level of proteolytic degradation by mucosal neutrophil elastase, along with a potential imbalance with elafin, contributes to the loss of function of biologic agents, which are currently used in patients with IBD. These findings might explain the non-responsiveness of UC patients to therapeutic monoclonal antibodies and suggest the potential beneficial concomitant use of elafin in this treatment.
publishDate 2020
dc.date.none.fl_str_mv 2020-05-22
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/11336/154829
Curciarello, Renata; Sobande, Toni; Jones, Samantha; Giuffrida, Paolo; Di Sabatino, Antonio; et al.; Human neutrophil elastase proteolytic activity in Ulcerative colitis favors the loss of function of therapeutic monoclonal antibodies; Dove Press; Journal of Inflammation Research; 13; 22-5-2020; 233-243
1178-7031
CONICET Digital
CONICET
url http://hdl.handle.net/11336/154829
identifier_str_mv Curciarello, Renata; Sobande, Toni; Jones, Samantha; Giuffrida, Paolo; Di Sabatino, Antonio; et al.; Human neutrophil elastase proteolytic activity in Ulcerative colitis favors the loss of function of therapeutic monoclonal antibodies; Dove Press; Journal of Inflammation Research; 13; 22-5-2020; 233-243
1178-7031
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/url/https://www.dovepress.com/articles.php?article_id=54030
info:eu-repo/semantics/altIdentifier/doi/10.2147/JIR.S234710
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Dove Press
publisher.none.fl_str_mv Dove Press
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 12.982451

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