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dc.contributor.author
Curciarello, Renata
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dc.contributor.author
Sobande, Toni
dc.contributor.author
Jones, Samantha
dc.contributor.author
Giuffrida, Paolo
dc.contributor.author
Di Sabatino, Antonio
dc.contributor.author
Docena, Guillermo H.
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dc.contributor.author
Macdonald, Thomas T.
dc.contributor.author
Klaartje, Kok
dc.date.available
2022-04-08T18:18:26Z
dc.date.issued
2020-05-22
dc.identifier.citation
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
dc.identifier.issn
1178-7031
dc.identifier.uri
http://hdl.handle.net/11336/154829
dc.description.abstract
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.
dc.format
application/pdf
dc.language.iso
eng
dc.publisher
Dove Press
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dc.rights
info:eu-repo/semantics/openAccess
dc.rights.uri
https://creativecommons.org/licenses/by-nc/2.5/ar/
dc.subject
ELASTINOLYTIC ACTIVITY
dc.subject
ELAFIN
dc.subject
ANTI-TNF
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INFLAMMATORY BOWEL DISEASE
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BIOLOGICAL DRUGS
dc.subject.classification
Inmunología
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dc.subject.classification
Medicina Básica
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CIENCIAS MÉDICAS Y DE LA SALUD
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dc.title
Human neutrophil elastase proteolytic activity in Ulcerative colitis favors the loss of function of therapeutic monoclonal antibodies
dc.type
info:eu-repo/semantics/article
dc.type
info:ar-repo/semantics/artículo
dc.type
info:eu-repo/semantics/publishedVersion
dc.date.updated
2021-09-06T17:49:34Z
dc.journal.volume
13
dc.journal.pagination
233-243
dc.journal.pais
Nueva Zelanda
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dc.journal.ciudad
Aukland
dc.description.fil
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
dc.description.fil
Fil: Sobande, Toni. University of London; Reino Unido
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Fil: Jones, Samantha. University of London; Reino Unido
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Fil: Giuffrida, Paolo. University of London; Reino Unido. Universita Degli Studi Di Pavia; Italia
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Fil: Di Sabatino, Antonio. Universita Degli Studi Di Pavia; Italia
dc.description.fil
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
dc.description.fil
Fil: Macdonald, Thomas T.. University of London; Reino Unido
dc.description.fil
Fil: Klaartje, Kok. University of London; Reino Unido. Royal London Hospital; Reino Unido
dc.journal.title
Journal of Inflammation Research
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/url/https://www.dovepress.com/articles.php?article_id=54030
dc.relation.alternativeid
info:eu-repo/semantics/altIdentifier/doi/http://dx.doi.org/10.2147/JIR.S234710
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