Anti-CD3 antibody treatment reduces scar formation in a rat model of myocardial infarction

Affiliation
Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria, bernhard_wernly@airpost.net
Wernly, Bernhard;
Affiliation
Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria, v.paar@salk.at
Paar, Vera;
GND
114228086
Affiliation
Rudolf Boehm-Institute for Pharmacology and Toxicology, Clinical Pharmacology, Leipzig University, Faculty of Medicine, 04107 Leipzig, Germany, Achim.Aigner@medizin.uni-leipzig.de
Aigner, Achim;
Affiliation
Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University Vienna, 1080 Vienna, Austria, patrick.pilz@meduniwien.ac.at
Pilz, Patrick M.;
Affiliation
Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University Vienna, 1080 Vienna, Austria, bruno.podesser@meduniwien.ac.at
Podesser, Bruno K;
Affiliation
Universitätsherzzentrum Thüringen, Clinic of Internal Medicine I, Department of Cardiology, Friedrich Schiller University Jena, 07743 Jena, Germany, Martin.Foerster@med.uni-jena.de
Förster, Martin;
GND
130020508
Affiliation
Division of Cardiology, Pulmonology, and Vascular Medicine University Duesseldorf, Medical Faculty, 40225 Duesseldorf, Germany, Christian.Jung@med.uni-duesseldorf.de
Jung, Christian;
Affiliation
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, j.d.pinon@salk.at
Pinon Hofbauer, Josefina;
Affiliation
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, b.tockner@salk.at
Tockner, Birgit;
Affiliation
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, m.wimmer@salk.at
Wimmer, Monika;
Affiliation
Department of Pathology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria, t.kraus@salk.at
Kraus, Theo;
Affiliation
Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria, l.motloch@salk.at
Motloch, Lukas J;
Affiliation
TAmiRNA GmbH, Leberstrasse 20, 1110 Vienna, Austria, matthias.hackl@tamirna.com
Hackl, Matthias;
Affiliation
Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria, u.hoppe@salk.at
Hoppe, Uta C;
Affiliation
Ludwig Boltzmann Institute for Cardiovascular Research at the Center for Biomedical Research, Medical University Vienna, 1080 Vienna, Austria, attila.kiss@meduniwien.ac.at
Kiss, Attila;
Affiliation
Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University Salzburg, 5020 Salzburg, Austria, michael.lichtenauer@chello.at
Lichtenauer, Michael

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.

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