In Vitro Transcribed mRNA Immunogenicity Induces Chemokine-Mediated Lymphocyte Recruitment and Can Be Gradually Tailored by Uridine Modification.
Adv Sci (Weinh)
; 11(21): e2308447, 2024 Jun.
Article
en En
| MEDLINE
| ID: mdl-38491873
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Uridina
/
ARN Mensajero
Límite:
Humans
Idioma:
En
Revista:
Adv Sci (Weinh)
Año:
2024
Tipo del documento:
Article
País de afiliación:
Alemania
Pais de publicación:
Alemania