Cargando…
Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction
Introduction: Antibody treatment with anti-thymocyte globulin (ATG) has been shown to be cardioprotective. We aimed to evaluate which single anti-T-cell epitope antibody alters chemokine expression at a level similar to ATG and identified CD3, which is a T-cell co-receptor mediating T-cell activatio...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2020
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072364/ https://www.ncbi.nlm.nih.gov/pubmed/31991811 http://dx.doi.org/10.3390/cells9020295 |
_version_ | 1783506389336850432 |
---|---|
author | Wernly, Bernhard Paar, Vera Aigner, Achim Pilz, Patrick M Podesser, Bruno K Förster, Martin Jung, Christian Pinon Hofbauer, Josefina Tockner, Birgit Wimmer, Monika Kraus, Theo Motloch, Lukas J Hackl, Matthias Hoppe, Uta C Kiss, Attila Lichtenauer, Michael |
author_facet | Wernly, Bernhard Paar, Vera Aigner, Achim Pilz, Patrick M Podesser, Bruno K Förster, Martin Jung, Christian Pinon Hofbauer, Josefina Tockner, Birgit Wimmer, Monika Kraus, Theo Motloch, Lukas J Hackl, Matthias Hoppe, Uta C Kiss, Attila Lichtenauer, Michael |
author_sort | Wernly, Bernhard |
collection | PubMed |
description | Introduction: Antibody treatment with anti-thymocyte globulin (ATG) has been shown to be cardioprotective. We aimed to evaluate which single anti-T-cell epitope antibody alters chemokine expression at a level similar to ATG and identified CD3, which is a T-cell co-receptor mediating T-cell activation. Based on these results, the effects of anti-CD3 antibody treatment on angiogenesis and cardioprotection were tested in vitro and in vivo. Methods: Concentrations of IL-8 and MCP-1 in supernatants of human peripheral blood mononuclear cell (PBMC) cultures following distinct antibody treatments were evaluated by Enzyme-linked Immunosorbent Assay (ELISA). In vivo, anti-CD3 antibodies or vehicle were injected intravenously in rats subjected to acute myocardial infarction (AMI). Chemotaxis and angiogenesis were evaluated using tube and migration assays. Intracellular pathways were assessed using Western blot. Extracellular vesicles (EVs) were quantitatively evaluated using fluorescence-activated cell scanning, exoELISA, and nanoparticle tracking analysis. Also, microRNA profiles were determined by next-generation sequencing. Results: Only PBMC stimulation with anti-CD3 antibody led to IL-8 and MCP-1 changes in secretion, similar to ATG. In a rat model of AMI, systemic treatment with an anti-CD3 antibody markedly reduced infarct scar size (27.8% (Inter-quartile range; IQR 16.2–34.9) vs. 12.6% (IQR 8.3–27.2); p < 0.01). The secretomes of anti-CD3 treated PBMC neither induced cardioprotective pathways in cardiomyocytes nor pro-angiogenic mechanisms in human umbilical vein endothelial cell (HUVECs) in vitro. While EVs quantities remained unchanged, PBMC incubation with an anti-CD3 antibody led to alterations in EVs miRNA expression. Conclusion: Treatment with an anti-CD3 antibody led to decreased scar size in a rat model of AMI. Whereas cardioprotective and pro-angiogenetic pathways were unaltered by anti-CD3 treatment, qualitative changes in the EVs miRNA expression could be observed, which might be causal for the observed cardioprotective phenotype. We provide evidence that EVs are a potential cardioprotective treatment target. Our findings will also provide the basis for a more detailed analysis of putatively relevant miRNA candidates. |
format | Online Article Text |
id | pubmed-7072364 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-70723642020-03-19 Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction Wernly, Bernhard Paar, Vera Aigner, Achim Pilz, Patrick M Podesser, Bruno K Förster, Martin Jung, Christian Pinon Hofbauer, Josefina Tockner, Birgit Wimmer, Monika Kraus, Theo Motloch, Lukas J Hackl, Matthias Hoppe, Uta C Kiss, Attila Lichtenauer, Michael Cells Article Introduction: Antibody treatment with anti-thymocyte globulin (ATG) has been shown to be cardioprotective. We aimed to evaluate which single anti-T-cell epitope antibody alters chemokine expression at a level similar to ATG and identified CD3, which is a T-cell co-receptor mediating T-cell activation. Based on these results, the effects of anti-CD3 antibody treatment on angiogenesis and cardioprotection were tested in vitro and in vivo. Methods: Concentrations of IL-8 and MCP-1 in supernatants of human peripheral blood mononuclear cell (PBMC) cultures following distinct antibody treatments were evaluated by Enzyme-linked Immunosorbent Assay (ELISA). In vivo, anti-CD3 antibodies or vehicle were injected intravenously in rats subjected to acute myocardial infarction (AMI). Chemotaxis and angiogenesis were evaluated using tube and migration assays. Intracellular pathways were assessed using Western blot. Extracellular vesicles (EVs) were quantitatively evaluated using fluorescence-activated cell scanning, exoELISA, and nanoparticle tracking analysis. Also, microRNA profiles were determined by next-generation sequencing. Results: Only PBMC stimulation with anti-CD3 antibody led to IL-8 and MCP-1 changes in secretion, similar to ATG. In a rat model of AMI, systemic treatment with an anti-CD3 antibody markedly reduced infarct scar size (27.8% (Inter-quartile range; IQR 16.2–34.9) vs. 12.6% (IQR 8.3–27.2); p < 0.01). The secretomes of anti-CD3 treated PBMC neither induced cardioprotective pathways in cardiomyocytes nor pro-angiogenic mechanisms in human umbilical vein endothelial cell (HUVECs) in vitro. While EVs quantities remained unchanged, PBMC incubation with an anti-CD3 antibody led to alterations in EVs miRNA expression. Conclusion: Treatment with an anti-CD3 antibody led to decreased scar size in a rat model of AMI. Whereas cardioprotective and pro-angiogenetic pathways were unaltered by anti-CD3 treatment, qualitative changes in the EVs miRNA expression could be observed, which might be causal for the observed cardioprotective phenotype. We provide evidence that EVs are a potential cardioprotective treatment target. Our findings will also provide the basis for a more detailed analysis of putatively relevant miRNA candidates. MDPI 2020-01-25 /pmc/articles/PMC7072364/ /pubmed/31991811 http://dx.doi.org/10.3390/cells9020295 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Wernly, Bernhard Paar, Vera Aigner, Achim Pilz, Patrick M Podesser, Bruno K Förster, Martin Jung, Christian Pinon Hofbauer, Josefina Tockner, Birgit Wimmer, Monika Kraus, Theo Motloch, Lukas J Hackl, Matthias Hoppe, Uta C Kiss, Attila Lichtenauer, Michael Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction |
title | Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction |
title_full | Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction |
title_fullStr | Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction |
title_full_unstemmed | Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction |
title_short | Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction |
title_sort | anti-cd3 antibody treatment reduces scar formation in a rat model of myocardial infarction |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072364/ https://www.ncbi.nlm.nih.gov/pubmed/31991811 http://dx.doi.org/10.3390/cells9020295 |
work_keys_str_mv | AT wernlybernhard anticd3antibodytreatmentreducesscarformationinaratmodelofmyocardialinfarction AT paarvera anticd3antibodytreatmentreducesscarformationinaratmodelofmyocardialinfarction AT aignerachim anticd3antibodytreatmentreducesscarformationinaratmodelofmyocardialinfarction AT pilzpatrickm anticd3antibodytreatmentreducesscarformationinaratmodelofmyocardialinfarction AT podesserbrunok anticd3antibodytreatmentreducesscarformationinaratmodelofmyocardialinfarction AT forstermartin anticd3antibodytreatmentreducesscarformationinaratmodelofmyocardialinfarction AT jungchristian anticd3antibodytreatmentreducesscarformationinaratmodelofmyocardialinfarction AT pinonhofbauerjosefina anticd3antibodytreatmentreducesscarformationinaratmodelofmyocardialinfarction AT tocknerbirgit anticd3antibodytreatmentreducesscarformationinaratmodelofmyocardialinfarction AT wimmermonika anticd3antibodytreatmentreducesscarformationinaratmodelofmyocardialinfarction AT kraustheo anticd3antibodytreatmentreducesscarformationinaratmodelofmyocardialinfarction AT motlochlukasj anticd3antibodytreatmentreducesscarformationinaratmodelofmyocardialinfarction AT hacklmatthias anticd3antibodytreatmentreducesscarformationinaratmodelofmyocardialinfarction AT hoppeutac anticd3antibodytreatmentreducesscarformationinaratmodelofmyocardialinfarction AT kissattila anticd3antibodytreatmentreducesscarformationinaratmodelofmyocardialinfarction AT lichtenauermichael anticd3antibodytreatmentreducesscarformationinaratmodelofmyocardialinfarction |