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Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy

OBJECTIVE: Activated synovial fibroblasts are key effector cells in RA. Selectively depleting these based upon their expression of fibroblast activation protein (FAP) is an attractive therapeutic approach. Here we introduce FAP imaging of inflamed joints using (68)Ga-FAPI-04 in a RA patient, and aim...

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Autores principales: Dorst, Daphne N, Rijpkema, Mark, Buitinga, Mijke, Walgreen, Birgitte, Helsen, Monique M A, Brennan, Evan, Klein, Christian, Laverman, Peter, Ramming, Andreas, Schmidkonz, Christian, Kuwert, Torsten, Schett, Georg, van der Kraan, Peter M, Gotthardt, Martin, Koenders, Marije I
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9258553/
https://www.ncbi.nlm.nih.gov/pubmed/34450633
http://dx.doi.org/10.1093/rheumatology/keab664
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author Dorst, Daphne N
Rijpkema, Mark
Buitinga, Mijke
Walgreen, Birgitte
Helsen, Monique M A
Brennan, Evan
Klein, Christian
Laverman, Peter
Ramming, Andreas
Schmidkonz, Christian
Kuwert, Torsten
Schett, Georg
van der Kraan, Peter M
Gotthardt, Martin
Koenders, Marije I
author_facet Dorst, Daphne N
Rijpkema, Mark
Buitinga, Mijke
Walgreen, Birgitte
Helsen, Monique M A
Brennan, Evan
Klein, Christian
Laverman, Peter
Ramming, Andreas
Schmidkonz, Christian
Kuwert, Torsten
Schett, Georg
van der Kraan, Peter M
Gotthardt, Martin
Koenders, Marije I
author_sort Dorst, Daphne N
collection PubMed
description OBJECTIVE: Activated synovial fibroblasts are key effector cells in RA. Selectively depleting these based upon their expression of fibroblast activation protein (FAP) is an attractive therapeutic approach. Here we introduce FAP imaging of inflamed joints using (68)Ga-FAPI-04 in a RA patient, and aim to assess feasibility of anti-FAP targeted photodynamic therapy (FAP-tPDT) ex vivo using 28H1-IRDye700DX on RA synovial explants. METHODS: Remnant synovial tissue from RA patients was processed into 6 mm biopsies and, from several patients, into primary fibroblast cell cultures. Both were treated using FAP-tPDT. Cell viability was measured in fibroblast cultures and biopsies were evaluated for histological markers of cell damage. Selectivity of the effect of FAP-tPDT was assessed using flow cytometry on primary fibroblasts and co-cultured macrophages. Additionally, one RA patient intravenously received (68)Ga-FAPI-04 and was scanned using PET/CT imaging. RESULTS: In the RA patient, FAPI-04 PET imaging showed high accumulation of the tracer in arthritic joints with very low background signal. In vitro, FAP-tPDT induced cell death in primary RA synovial fibroblasts in a light dose-dependent manner. An upregulation of cell damage markers was observed in the synovial biopsies after FAP-tPDT. No significant effects of FAP-tPDT were noted on macrophages after FAP-tPDT of neighbouring fibroblasts. CONCLUSION: In this study the feasibility of selective FAP-tPDT in synovium of rheumatoid arthritis patients ex vivo is demonstrated. Furthermore, this study provides the first indication that FAP-targeted PET/CT can be used to image arthritic joints, an important step towards application of FAP-tPDT as a targeted locoregional therapy for RA.
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spelling pubmed-92585532022-07-07 Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy Dorst, Daphne N Rijpkema, Mark Buitinga, Mijke Walgreen, Birgitte Helsen, Monique M A Brennan, Evan Klein, Christian Laverman, Peter Ramming, Andreas Schmidkonz, Christian Kuwert, Torsten Schett, Georg van der Kraan, Peter M Gotthardt, Martin Koenders, Marije I Rheumatology (Oxford) Basic Science OBJECTIVE: Activated synovial fibroblasts are key effector cells in RA. Selectively depleting these based upon their expression of fibroblast activation protein (FAP) is an attractive therapeutic approach. Here we introduce FAP imaging of inflamed joints using (68)Ga-FAPI-04 in a RA patient, and aim to assess feasibility of anti-FAP targeted photodynamic therapy (FAP-tPDT) ex vivo using 28H1-IRDye700DX on RA synovial explants. METHODS: Remnant synovial tissue from RA patients was processed into 6 mm biopsies and, from several patients, into primary fibroblast cell cultures. Both were treated using FAP-tPDT. Cell viability was measured in fibroblast cultures and biopsies were evaluated for histological markers of cell damage. Selectivity of the effect of FAP-tPDT was assessed using flow cytometry on primary fibroblasts and co-cultured macrophages. Additionally, one RA patient intravenously received (68)Ga-FAPI-04 and was scanned using PET/CT imaging. RESULTS: In the RA patient, FAPI-04 PET imaging showed high accumulation of the tracer in arthritic joints with very low background signal. In vitro, FAP-tPDT induced cell death in primary RA synovial fibroblasts in a light dose-dependent manner. An upregulation of cell damage markers was observed in the synovial biopsies after FAP-tPDT. No significant effects of FAP-tPDT were noted on macrophages after FAP-tPDT of neighbouring fibroblasts. CONCLUSION: In this study the feasibility of selective FAP-tPDT in synovium of rheumatoid arthritis patients ex vivo is demonstrated. Furthermore, this study provides the first indication that FAP-targeted PET/CT can be used to image arthritic joints, an important step towards application of FAP-tPDT as a targeted locoregional therapy for RA. Oxford University Press 2021-08-27 /pmc/articles/PMC9258553/ /pubmed/34450633 http://dx.doi.org/10.1093/rheumatology/keab664 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Rheumatology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com
spellingShingle Basic Science
Dorst, Daphne N
Rijpkema, Mark
Buitinga, Mijke
Walgreen, Birgitte
Helsen, Monique M A
Brennan, Evan
Klein, Christian
Laverman, Peter
Ramming, Andreas
Schmidkonz, Christian
Kuwert, Torsten
Schett, Georg
van der Kraan, Peter M
Gotthardt, Martin
Koenders, Marije I
Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy
title Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy
title_full Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy
title_fullStr Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy
title_full_unstemmed Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy
title_short Targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy
title_sort targeting of fibroblast activation protein in rheumatoid arthritis patients: imaging and ex vivo photodynamic therapy
topic Basic Science
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9258553/
https://www.ncbi.nlm.nih.gov/pubmed/34450633
http://dx.doi.org/10.1093/rheumatology/keab664
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