In Vitro Transcribed mRNA Immunogenicity Induces Chemokine-Mediated Lymphocyte Recruitment and Can Be Gradually Tailored by Uridine Modification.

Autor: Drzeniek NM; Charité - Universitätsmedizin Berlin, corporate member of Freie Universitaet Berlin and Humboldt-Universitaet zu Berlin, Institute of Medical Immunology, Augustenburger Platz 1, 13353, Berlin, Germany.; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Föhrer Straße 15, 13353, Berlin, Germany., Kahwaji N; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Föhrer Straße 15, 13353, Berlin, Germany., Picht S; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Föhrer Straße 15, 13353, Berlin, Germany.; Berlin-Brandenburg School for Regenerative Therapies (BSRT; graduate school 203 of the German Excellence Initiative), Augustenburger Platz 1, 13353, Berlin, Germany., Dimitriou IM; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Föhrer Straße 15, 13353, Berlin, Germany.; Berlin-Brandenburg School for Regenerative Therapies (BSRT; graduate school 203 of the German Excellence Initiative), Augustenburger Platz 1, 13353, Berlin, Germany.; Julius Wolff Institute (JWI), Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.; Department of Biology, Chemistry, Pharmacy, Institute of Chemistry and Biochemistry, Freie Universität Berlin, Thielallee 63, 14195, Berlin, Germany., Schlickeiser S; Charité - Universitätsmedizin Berlin, corporate member of Freie Universitaet Berlin and Humboldt-Universitaet zu Berlin, Institute of Medical Immunology, Augustenburger Platz 1, 13353, Berlin, Germany.; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Föhrer Straße 15, 13353, Berlin, Germany.; CheckImmune GmbH, Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany., Moradian H; Institute of Active Polymers, Helmholtz-Zentrum Hereon, Kantstraße 55, 14513, Teltow, Germany.; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353, Berlin, Germany., Geissler S; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Föhrer Straße 15, 13353, Berlin, Germany.; Julius Wolff Institute (JWI), Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Augustenburger Platz 1, 13353, Berlin, Germany.; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Center for Advanced Therapies (BeCAT), Augustenburger Platz 1, 13353, Berlin, Germany., Schmueck-Henneresse M; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Föhrer Straße 15, 13353, Berlin, Germany.; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Center for Advanced Therapies (BeCAT), Augustenburger Platz 1, 13353, Berlin, Germany., Gossen M; Institute of Active Polymers, Helmholtz-Zentrum Hereon, Kantstraße 55, 14513, Teltow, Germany.; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Augustenburger Platz 1, 13353, Berlin, Germany., Volk HD; Charité - Universitätsmedizin Berlin, corporate member of Freie Universitaet Berlin and Humboldt-Universitaet zu Berlin, Institute of Medical Immunology, Augustenburger Platz 1, 13353, Berlin, Germany.; Berlin Institute of Health at Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Föhrer Straße 15, 13353, Berlin, Germany.; CheckImmune GmbH, Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany.; Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin Center for Advanced Therapies (BeCAT), Augustenburger Platz 1, 13353, Berlin, Germany.
Jazyk: angličtina
Zdroj: Advanced science (Weinheim, Baden-Wurttemberg, Germany) [Adv Sci (Weinh)] 2024 Jun; Vol. 11 (21), pp. e2308447. Date of Electronic Publication: 2024 Mar 16.
DOI: 10.1002/advs.202308447
Abstrakt: Beyond SARS-CoV2 vaccines, mRNA drugs are being explored to overcome today's greatest healthcare burdens, including cancer and cardiovascular disease. Synthetic mRNA triggers immune responses in transfected cells, which can be reduced by chemically modified nucleotides. However, the side effects of mRNA-triggered immune activation on cell function and how different nucleotides, such as the N1-methylpseudouridine (m1Ψ) used in SARS-CoV2 vaccines, can modulate cellular responses is not fully understood. Here, cellular responses toward a library of uridine-modified mRNAs are investigated in primary human cells. Targeted proteomics analyses reveal that unmodified mRNA induces a pro-inflammatory paracrine pattern marked by the secretion of chemokines, which recruit T and B lymphocytes toward transfected cells. Importantly, the magnitude of mRNA-induced changes in cell function varies quantitatively between unmodified, Ψ-, m1Ψ-, and 5moU-modified mRNA and can be gradually tailored, with implications for deliberately exploiting this effect in mRNA drug design. Indeed, both the immunosuppressive effect of stromal cells on T-cell proliferation, and the anti-inflammatory effect of IL-10 mRNA are enhanced by appropriate uridine modification. The results provide new insights into the effects of mRNA drugs on cell function and cell-cell communication and open new possibilities to tailor mRNA-triggered immune activation to the desired pro- or anti-inflammatory application.
(© 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.)
Databáze: MEDLINE
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