Lena Peter, Désirée Jacqueline Wendering, Stephan Schlickeiser, Henrike Hoffmann, Rebecca Noster, Dimitrios Laurin Wagner, Ghazaleh Zarrinrad, Sandra Münch, Samira Picht, Sarah Schulenberg, Hanieh Moradian, Mir-Farzin Mashreghi, Oliver Klein, Manfred Gossen, Toralf Roch, Nina Babel, Petra Reinke, Hans-Dieter Volk, Leila Amini, Michael Schmueck-Henneresse
- Solid organ transplant (SOT) recipients receive therapeutic immunosuppression that compromises their immune response to infections and vaccines. For this reason, SOT patients have a high risk of developing severe coronavirus disease 2019 (COVID-19) and an increased risk of death from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Moreover, the efficiency of immunotherapies and vaccines is reduced due to the constant immunosuppression in this patient group. Here, we propose adoptive transfer of SARS-CoV-2-specific T cells made resistant to a common immunosuppressant, tacrolimus, for optimized performance in the immunosuppressed patient. Using a ribonucleoprotein approach of CRISPR-Cas9 technology, we have generated tacrolimus-resistant SARS-CoV-2-specific T cell products from convalescent donors and demonstrate their specificity and function through characterizations at the single-cell level, including flow cytometry, single-cell RNA (scRNA) Cellular Indexing of Transcriptomes and Epitopes (CITE), and T cellSolid organ transplant (SOT) recipients receive therapeutic immunosuppression that compromises their immune response to infections and vaccines. For this reason, SOT patients have a high risk of developing severe coronavirus disease 2019 (COVID-19) and an increased risk of death from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Moreover, the efficiency of immunotherapies and vaccines is reduced due to the constant immunosuppression in this patient group. Here, we propose adoptive transfer of SARS-CoV-2-specific T cells made resistant to a common immunosuppressant, tacrolimus, for optimized performance in the immunosuppressed patient. Using a ribonucleoprotein approach of CRISPR-Cas9 technology, we have generated tacrolimus-resistant SARS-CoV-2-specific T cell products from convalescent donors and demonstrate their specificity and function through characterizations at the single-cell level, including flow cytometry, single-cell RNA (scRNA) Cellular Indexing of Transcriptomes and Epitopes (CITE), and T cell receptor (TCR) sequencing analyses. Based on the promising results, we aim for clinical validation of this approach in transplant recipients. Additionally, we propose a combinatory approach with tacrolimus, to prevent an overshooting immune response manifested as bystander T cell activation in the setting of severe COVID-19 immunopathology, and tacrolimus-resistant SARS-CoV-2-specific T cell products, allowing for efficient clearance of viral infection. Our strategy has the potential to prevent severe COVID-19 courses in SOT or autoimmunity settings and to prevent immunopathology while providing viral clearance in severe non-transplant COVID-19 cases.…
MetadatenAuthor details: | Lena Peter, Désirée Jacqueline Wendering, Stephan Schlickeiser, Henrike Hoffmann, Rebecca Noster, Dimitrios Laurin Wagner, Ghazaleh Zarrinrad, Sandra Münch, Samira Picht, Sarah SchulenbergORCiD, Hanieh MoradianORCiDGND, Mir-Farzin Mashreghi, Oliver Klein, Manfred Gossen, Toralf Roch, Nina Babel, Petra Reinke, Hans-Dieter VolkORCiD, Leila Amini, Michael Schmueck-HenneresseORCiD |
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DOI: | https://doi.org/10.1016/j.omtm.2022.02.012 |
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ISSN: | 2329-0501 |
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Pubmed ID: | https://pubmed.ncbi.nlm.nih.gov/35252469 |
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Title of parent work (English): | Molecular therapy methods and clinical development |
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Publisher: | Cell Press |
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Place of publishing: | Cambridge |
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Publication type: | Article |
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Language: | English |
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Date of first publication: | 2022/03/16 |
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Publication year: | 2022 |
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Release date: | 2024/06/24 |
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Volume: | 25 |
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Number of pages: | 22 |
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First page: | 52 |
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Last Page: | 73 |
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Funding institution: | German Federal Ministry of Education and Research (BIH Center for; Regenerative Therapies, Berlin); Einstein Center for Regenerative; Therapies; state of Berlin; European Regional Development Fund (ERDF; 2014-2020) [EFRE 1.8/11]; Berlin Institute of Health (BIH); BIH; Translation-Mission-Fund; Crossfield project fund of the BIH Research; Focus Regenerative Medicine; BIH Research Platform Clinical; Translational Sciences grant; Federal Ministry of Education and Research; [01EK2104A] |
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Organizational units: | Mathematisch-Naturwissenschaftliche Fakultät / Institut für Biochemie und Biologie |
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DDC classification: | 5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie |
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Peer review: | Referiert |
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Publishing method: | Open Access / Gold Open-Access |
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| DOAJ gelistet |
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License (German): | CC-BY-NC-ND - Namensnennung, nicht kommerziell, keine Bearbeitungen 4.0 International |
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