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Open AccessArticle

Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction

1
Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
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Division of Cardiology, Department of Medicine, Karolinska Institutet, Karolinska University Hospital, 171 77 Stockholm, Sweden
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Rudolf Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig University, Faculty of Medicine, 04107 Leipzig, Germany
4
Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University Vienna, 1080 Vienna, Austria
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Universitätsherzzentrum Thüringen, Clinic of Internal Medicine I, Department of Cardiology, Friedrich Schiller University Jena, 07743 Jena, Germany
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Division of Cardiology, Pulmonology, and Vascular Medicine University Duesseldorf, Medical Faculty, 40225 Duesseldorf, Germany
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EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
8
Department of Pathology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria
9
TAmiRNA GmbH, Leberstrasse 20, 1110 Vienna, Austria
*
Author to whom correspondence should be addressed.
Cells 2020, 9(2), 295; https://doi.org/10.3390/cells9020295
Received: 31 December 2019 / Revised: 18 January 2020 / Accepted: 21 January 2020 / Published: 25 January 2020
(This article belongs to the Special Issue Cells in Cardiovascular Disease)
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. View Full-Text
Keywords: myocardial infarction; CD3; anti-CD; antibody treatment; cardioprotection; AMI; apoptosis; angiogenesis; miRNA myocardial infarction; CD3; anti-CD; antibody treatment; cardioprotection; AMI; apoptosis; angiogenesis; miRNA
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Wernly, B.; Paar, V.; Aigner, A.; Pilz, P.M.; Podesser, B.K.; Förster, M.; Jung, C.; Pinon Hofbauer, J.; Tockner, B.; Wimmer, M.; Kraus, T.; Motloch, L.J.; Hackl, M.; Hoppe, U.C.; Kiss, A.; Lichtenauer, M. Anti-CD3 Antibody Treatment Reduces Scar Formation in a Rat Model of Myocardial Infarction. Cells 2020, 9, 295.

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