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Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models

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Almholt, K, Hebsgaard, JB, Nansen, A, Andersson, C, Pass, J, Rønø, B, Thygesen, P, Pelzer, H, Loftager, M, Lund, IK, Høyer-Hansen, G, Frisch, T, Jensen, CH, Otte, KS, Søe, NH, Bartels, EM, Andersen, M, Bliddal, H & Usher, PA 2018, 'Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models' Journal of immunology (Baltimore, Md. : 1950), bind 200, nr. 3, s. 957-965. https://doi.org/10.4049/jimmunol.1701317

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Almholt, Kasper ; Hebsgaard, Josephine B ; Nansen, Anneline ; Andersson, Christina ; Pass, Jesper ; Rønø, Birgitte ; Thygesen, Peter ; Pelzer, Hermann ; Loftager, Mette ; Lund, Ida K ; Høyer-Hansen, Gunilla ; Frisch, Thomas ; Jensen, Claus H ; Otte, Kristian S ; Søe, Niels H ; Bartels, Else M ; Andersen, Martin ; Bliddal, Henning ; Usher, Pernille A. / Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models. I: Journal of immunology (Baltimore, Md. : 1950). 2018 ; Bind 200, Nr. 3. s. 957-965.

Bibtex

@article{9c527f15a3c447b696b1a4caf0e1b405,
title = "Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models",
abstract = "Genetic absence of the urokinase-type plasminogen activator (uPA) reduces arthritis progression in the collagen-induced arthritis (CIA) mouse model to an extent just shy of disease abrogation, but this remarkable observation has not been translated into therapeutic intervention. Our aim was to test the potential in mice of an Ab that blocks the proteolytic capacity of uPA in the CIA model and the delayed-type hypersensitivity arthritis model. A second aim was to determine the cellular origins of uPA and the uPA receptor (uPAR) in joint tissue from patients with rheumatoid arthritis. A mAb that neutralizes mouse uPA significantly reduced arthritis progression in the CIA and delayed-type hypersensitivity arthritis models. In the CIA model, the impact of anti-uPA treatment was on par with the effect of blocking TNF-α by etanercept. A pharmacokinetics evaluation of the therapeutic Ab revealed target-mediated drug disposition consistent with a high turnover of endogenous uPA. The cellular expression patterns of uPA and uPAR were characterized by double immunofluorescence in the inflamed synovium from patients with rheumatoid arthritis and compared with synovium from healthy donors. The arthritic synovium showed expression of uPA and uPAR in neutrophils, macrophages, and a fraction of endothelial cells, whereas there was little or no expression in synovium from healthy donors. The data from animal models and human material provide preclinical proof-of-principle that validates uPA as a novel therapeutic target in rheumatic diseases.",
keywords = "Journal Article",
author = "Kasper Almholt and Hebsgaard, {Josephine B} and Anneline Nansen and Christina Andersson and Jesper Pass and Birgitte R{\o}n{\o} and Peter Thygesen and Hermann Pelzer and Mette Loftager and Lund, {Ida K} and Gunilla H{\o}yer-Hansen and Thomas Frisch and Jensen, {Claus H} and Otte, {Kristian S} and S{\o}e, {Niels H} and Bartels, {Else M} and Martin Andersen and Henning Bliddal and Usher, {Pernille A}",
note = "Copyright {\circledC} 2017 by The American Association of Immunologists, Inc.",
year = "2018",
month = "2",
day = "1",
doi = "10.4049/jimmunol.1701317",
language = "English",
volume = "200",
pages = "957--965",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "3",

}

RIS

TY - JOUR

T1 - Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models

AU - Almholt, Kasper

AU - Hebsgaard, Josephine B

AU - Nansen, Anneline

AU - Andersson, Christina

AU - Pass, Jesper

AU - Rønø, Birgitte

AU - Thygesen, Peter

AU - Pelzer, Hermann

AU - Loftager, Mette

AU - Lund, Ida K

AU - Høyer-Hansen, Gunilla

AU - Frisch, Thomas

AU - Jensen, Claus H

AU - Otte, Kristian S

AU - Søe, Niels H

AU - Bartels, Else M

AU - Andersen, Martin

AU - Bliddal, Henning

AU - Usher, Pernille A

N1 - Copyright © 2017 by The American Association of Immunologists, Inc.

PY - 2018/2/1

Y1 - 2018/2/1

N2 - Genetic absence of the urokinase-type plasminogen activator (uPA) reduces arthritis progression in the collagen-induced arthritis (CIA) mouse model to an extent just shy of disease abrogation, but this remarkable observation has not been translated into therapeutic intervention. Our aim was to test the potential in mice of an Ab that blocks the proteolytic capacity of uPA in the CIA model and the delayed-type hypersensitivity arthritis model. A second aim was to determine the cellular origins of uPA and the uPA receptor (uPAR) in joint tissue from patients with rheumatoid arthritis. A mAb that neutralizes mouse uPA significantly reduced arthritis progression in the CIA and delayed-type hypersensitivity arthritis models. In the CIA model, the impact of anti-uPA treatment was on par with the effect of blocking TNF-α by etanercept. A pharmacokinetics evaluation of the therapeutic Ab revealed target-mediated drug disposition consistent with a high turnover of endogenous uPA. The cellular expression patterns of uPA and uPAR were characterized by double immunofluorescence in the inflamed synovium from patients with rheumatoid arthritis and compared with synovium from healthy donors. The arthritic synovium showed expression of uPA and uPAR in neutrophils, macrophages, and a fraction of endothelial cells, whereas there was little or no expression in synovium from healthy donors. The data from animal models and human material provide preclinical proof-of-principle that validates uPA as a novel therapeutic target in rheumatic diseases.

AB - Genetic absence of the urokinase-type plasminogen activator (uPA) reduces arthritis progression in the collagen-induced arthritis (CIA) mouse model to an extent just shy of disease abrogation, but this remarkable observation has not been translated into therapeutic intervention. Our aim was to test the potential in mice of an Ab that blocks the proteolytic capacity of uPA in the CIA model and the delayed-type hypersensitivity arthritis model. A second aim was to determine the cellular origins of uPA and the uPA receptor (uPAR) in joint tissue from patients with rheumatoid arthritis. A mAb that neutralizes mouse uPA significantly reduced arthritis progression in the CIA and delayed-type hypersensitivity arthritis models. In the CIA model, the impact of anti-uPA treatment was on par with the effect of blocking TNF-α by etanercept. A pharmacokinetics evaluation of the therapeutic Ab revealed target-mediated drug disposition consistent with a high turnover of endogenous uPA. The cellular expression patterns of uPA and uPAR were characterized by double immunofluorescence in the inflamed synovium from patients with rheumatoid arthritis and compared with synovium from healthy donors. The arthritic synovium showed expression of uPA and uPAR in neutrophils, macrophages, and a fraction of endothelial cells, whereas there was little or no expression in synovium from healthy donors. The data from animal models and human material provide preclinical proof-of-principle that validates uPA as a novel therapeutic target in rheumatic diseases.

KW - Journal Article

U2 - 10.4049/jimmunol.1701317

DO - 10.4049/jimmunol.1701317

M3 - Journal article

VL - 200

SP - 957

EP - 965

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 3

ER -

ID: 52347779