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

Norman Michael Drzeniek; Nourhan Kahwaji; Samira Picht; Ioanna Maria Dimitriou; Stephan Schlickeiser; Hanieh Moradian; Sven Geissler; Michael Schmueck‐Henneresse; Manfred Gossen; Hans‐Dieter Volk

doi:10.1002/advs.202308447

journal article Open Access Mar 16, 2024

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

Norman Michael Drzeniek

Nourhan Kahwaji

Samira Picht Ioanna Maria Dimitriou Stephan Schlickeiser

Hanieh Moradian

Sven Geissler

Michael Schmueck‐Henneresse Manfred Gossen

Hans‐Dieter Volk

Advanced Science Vol. 11 No. 21 · Wiley

View at Publisher Save 10.1002/advs.202308447

Abstract

AbstractBeyond 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.

Topics

No keywords indexed for this article. Browse by subject →

References

48

[1]

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Lindsey R. Baden, Hana M. El Sahly, Brandon Essink et al.

New England Journal of Medicine 10.1056/nejmoa2035389

[2]

10.1126/science.aay5967

[3]

Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer

Luis A. Rojas, Zachary Sethna, Kevin C. Soares et al.

Nature 10.1038/s41586-023-06063-y

[4]

10.1038/s41573-021-00355-6

[5]

10.1016/j.omtm.2020.05.030

[6]

10.1182/blood-2013-04-495119

[7]

10.1038/nbt.2682

[8]

10.1016/j.bbrc.2010.02.150

[9]

10.1158/1078-0432.ccr-21-4384

[10]

CAR T cells produced in vivo to treat cardiac injury

Joel G. Rurik, István Tombácz, Amir Yadegari et al.

Science 10.1126/science.abm0594

[11]

10.1172/jci61852

[12]

10.1038/nbt.4207

[13]

10.1021/acs.bioconjchem.6b00090

[14]

10.1016/j.omtn.2021.07.009

[15]

10.1016/j.tcb.2015.02.001

[16]

Immuno-engineered mRNA combined with cell adhesive niche for synergistic modulation of the MSC secretome

Norman Michael Drzeniek, Nourhan Kahwaji, Stephan Schlickeiser et al.

Biomaterials 10.1016/j.biomaterials.2022.121971

[17]

10.1021/acs.nanolett.9b04246

[18]

10.1038/s41467-019-08852-4

[19]

Suppression of RNA Recognition by Toll-like Receptors: The Impact of Nucleoside Modification and the Evolutionary Origin of RNA

Katalin Karikó, Michael Buckstein, Houping Ni et al.

Immunity 10.1016/j.immuni.2005.06.008

[20]

Incorporation of pseudouridine into mRNA enhances translation by diminishing PKR activation

Bart R. Anderson, Hiromi Muramatsu, Subba R. Nallagatla et al.

Nucleic Acids Research 10.1093/nar/gkq347

[21]

Modifications in an Emergency: The Role of N1-Methylpseudouridine in COVID-19 Vaccines

Kellie D. Nance, Jordan L. Meier

ACS Central Science 10.1021/acscentsci.1c00197

[22]

10.1016/j.jconrel.2015.08.051

[23]

N1-methyl-pseudouridine in mRNA enhances translation through eIF2α-dependent and independent mechanisms by increasing ribosome density

Yuri V. Svitkin, Yi Min Cheng, Tirtha Chakraborty et al.

Nucleic Acids Research 10.1093/nar/gkx135

[24]

Mesenchymal Stromal Cells: Clinical Challenges and Therapeutic Opportunities

Jacques Galipeau, Luc Sensébé

Cell Stem Cell 10.1016/j.stem.2018.05.004

[25]

10.3390/cells10113101

[26]

10.1124/pr.55.2.4

[27]

10.1038/nri2436

[28]

10.1038/nrmicro2655

[29]

Nucleoside modifications in RNA limit activation of 2'-5'-oligoadenylate synthetase and increase resistance to cleavage by RNase L

B. R. Anderson, H. Muramatsu, B. K. Jha et al.

Nucleic Acids Research 10.1093/nar/gkr586

[30]

10.1002/eji.200737744

[31]

10.1128/jvi.02133-10

[32]

10.1371/journal.pone.0011756

[33]

10.1042/bc20080221

[34]

10.1126/scitranslmed.3000112

[35]

The intratumoral CXCR3 chemokine system is predictive of chemotherapy response in human bladder cancer

Tino Vollmer, Stephan Schlickeiser, Leila Amini et al.

Science Translational Medicine 10.1126/scitranslmed.abb3735

[36]

10.3389/fimmu.2019.02474

[37]

10.1097/shk.0000000000000557

[38]

10.1038/nm0697-678

[39]

10.1136/thx.51.2.143

[40]

10.3389/fimmu.2022.983000

[41]

10.1126/scitranslmed.3004754

[42]

10.1002/term.1505

[43]

10.1038/mt.2015.103

[44]

10.1186/ar2823

[45]

10.1084/jem.187.4.655

[46]

Of Mice and Not Men: Differences between Mouse and Human Immunology

Javier Mestas, Christopher C W Hughes

The Journal of Immunology 10.4049/jimmunol.172.5.2731

[47]

10.1088/1758-5090/ac0a32

[48]

10.3389/fnins.2010.00181

Metrics

16

Citations

48

References

Details

Published: Mar 16, 2024
Vol/Issue: 11(21)
License: View

Authors

N

Norman Michael Drzeniek

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

N

Nourhan Kahwaji

Berlin Institute of Health at Charité – Universitätsmedizin Berlin BIH Center for Regenerative Therapies (BCRT) Föhrer Straße 15 13353 Berlin Germany

S

Samira Picht

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

I

Ioanna Maria Dimitriou

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

S

Stephan Schlickeiser

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

H

Hanieh Moradian

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

S

Sven Geissler

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

M

Michael Schmueck‐Henneresse

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

M

Manfred Gossen

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

H

Hans‐Dieter Volk

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

Funding

Deutsche Forschungsgemeinschaft Award: CollaborativeResearchCenter1444(CRC1444)

Horizon 2020 Framework Programme Award: 733006

Einstein Stiftung Berlin Award: Advanced_Scientist_Kickbox

European Health and Digital Executive Agency Award: 101095635—PROTO

Cite This Article

Norman Michael Drzeniek, Nourhan Kahwaji, Samira Picht, et al. (2024). In Vitro Transcribed mRNA Immunogenicity Induces Chemokine‐Mediated Lymphocyte Recruitment and Can Be Gradually Tailored by Uridine Modification. Advanced Science, 11(21). https://doi.org/10.1002/advs.202308447

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

You May Also Like