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 © 2018 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-a 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-a 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 - Animals
KW - Antibodies, Monoclonal/immunology
KW - Arthritis, Experimental/pathology
KW - Arthritis, Rheumatoid/pathology
KW - Disease Models, Animal
KW - Disease Progression
KW - Endothelial Cells/immunology
KW - Etanercept/pharmacology
KW - Female
KW - Humans
KW - Hypersensitivity, Delayed/immunology
KW - Macrophages/immunology
KW - Male
KW - Mice
KW - Mice, Inbred C57BL
KW - Mice, Inbred DBA
KW - Neutrophils/immunology
KW - Receptors, Urokinase Plasminogen Activator/metabolism
KW - Synovial Membrane/immunology
KW - Tumor Necrosis Factor-alpha/antagonists & inhibitors
KW - Urokinase-Type Plasminogen Activator/antagonists & inhibitors
U2 - 10.4049/jimmunol.1701317
DO - 10.4049/jimmunol.1701317
M3 - Journal article
C2 - 29282305
SN - 0022-1767
VL - 200
SP - 957
EP - 965
JO - The Journal of Immunology
JF - The Journal of Immunology
IS - 3
ER -
