Human Neutrophil Elastase Proteolytic Activity in Ulcerative Colitis Favors the Loss of Function of Therapeutic Monoclonal Antibodies

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 in...

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Autores principales: Curciarello, Renata, Sobande, Toni, Jones, Samantha, Giuffrida, Paolo, Di Sabatino, Antonio, Docena, Guillermo Horacio, MacDonald, Thomas T., Kok, Klaartje
Formato: Articulo
Lenguaje:Inglés
Publicado: 2020
Materias:
Ciencias Exactas
Ciencias Médicas
elastinolytic activity
elafin
anti-TNF
inflammatory bowel disease
biological drugs
Acceso en línea:http://sedici.unlp.edu.ar/handle/10915/107870
http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC7251227&blobtype=pdf
https://www.dovepress.com/human-neutrophil-elastase-proteolytic-activity-in-ulcerative-colitis-f-peer-reviewed-article-JIR
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SEDICI (UNLP) de Universidad Nacional de La Plata
id I19-R120-10915-107870
record_format dspace
institution Universidad Nacional de La Plata
institution_str I-19
repository_str R-120
collection SEDICI (UNLP)
language Inglés
topic Ciencias Exactas
Ciencias Médicas
elastinolytic activity
elafin
anti-TNF
inflammatory bowel disease
biological drugs
spellingShingle Ciencias Exactas
Ciencias Médicas
elastinolytic activity
elafin
anti-TNF
inflammatory bowel disease
biological drugs
Curciarello, Renata
Sobande, Toni
Jones, Samantha
Giuffrida, Paolo
Di Sabatino, Antonio
Docena, Guillermo Horacio
MacDonald, Thomas T.
Kok, Klaartje
Human Neutrophil Elastase Proteolytic Activity in Ulcerative Colitis Favors the Loss of Function of Therapeutic Monoclonal Antibodies
topic_facet Ciencias Exactas
Ciencias Médicas
elastinolytic activity
elafin
anti-TNF
inflammatory bowel disease
biological drugs
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.
format Articulo
Articulo
author Curciarello, Renata
Sobande, Toni
Jones, Samantha
Giuffrida, Paolo
Di Sabatino, Antonio
Docena, Guillermo Horacio
MacDonald, Thomas T.
Kok, Klaartje
author_facet Curciarello, Renata
Sobande, Toni
Jones, Samantha
Giuffrida, Paolo
Di Sabatino, Antonio
Docena, Guillermo Horacio
MacDonald, Thomas T.
Kok, Klaartje
author_sort Curciarello, Renata
title Human Neutrophil Elastase Proteolytic Activity in Ulcerative Colitis Favors the Loss of Function of Therapeutic Monoclonal Antibodies
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
publishDate 2020
url http://sedici.unlp.edu.ar/handle/10915/107870
http://europepmc.org/backend/ptpmcrender.fcgi?accid=PMC7251227&blobtype=pdf
https://www.dovepress.com/human-neutrophil-elastase-proteolytic-activity-in-ulcerative-colitis-f-peer-reviewed-article-JIR
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