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Particle-mediated intravenous delivery of antigen mRNA results in strong antigen-specific T-cell responses despite the induction of type I interferon

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Abstract
Cancer vaccines based on mRNA are extensively studied. The fragile nature of mRNA has instigated research into carriers that can protect it from ribonucleases and as such enable its systemic use. However, carrier-mediated delivery of mRNA has been linked to production of type I interferon (IFN) that was reported to compromise the effectiveness of mRNA vaccines. In this study, we evaluated a cationic lipid for encapsulation of mRNA. The nanometer-sized, negatively charged lipid mRNA particles (LMPs) efficiently transfected dendritic cells and macrophages in vitro. Furthermore, i.v. delivery of LMPs resulted in rapid expression of the mRNA-encoded protein in spleen and liver, predominantly in CD11c+ cells and to a minor extent in CD11b+ cells. Intravenous immunization of mice with LMPs containing ovalbumin, human papilloma virus E7, and tyrosinase related protein-2 mRNA, either combined or separately, elicited strong antigen-specific T-cell responses. We further showed the production of type I IFNs upon i.v. LMP delivery. Although this decreased the expression of the mRNA-encoded protein, it supported the induction of antigen-specific T-cell responses. These data question the current notion that type I IFNs hamper particle-mediated mRNA vaccines.
Keywords
particle, type I interferon, cytotoxic T lymphocyte, immunotherapy, mRNA, liposome

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Citation

Please use this url to cite or link to this publication:

Chicago
Broos, Katrijn, Kevin Vanderjeught, Janik Puttemans, Cleo Goyvaerts, Carlo Heirman, Heleen Dewitte, Rein Verbeke, Ine Lentacker, Kris Thielemans, and Karine Breckpot. 2016. “Particle-mediated Intravenous Delivery of Antigen mRNA Results in Strong Antigen-specific T-cell Responses Despite the Induction of Type I Interferon.” Molecular Therapy-nucleic Acids 5.
APA
Broos, Katrijn, Vanderjeught, K., Puttemans, J., Goyvaerts, C., Heirman, C., Dewitte, H., Verbeke, R., et al. (2016). Particle-mediated intravenous delivery of antigen mRNA results in strong antigen-specific T-cell responses despite the induction of type I interferon. MOLECULAR THERAPY-NUCLEIC ACIDS, 5.
Vancouver
1.
Broos K, Vanderjeught K, Puttemans J, Goyvaerts C, Heirman C, Dewitte H, et al. Particle-mediated intravenous delivery of antigen mRNA results in strong antigen-specific T-cell responses despite the induction of type I interferon. MOLECULAR THERAPY-NUCLEIC ACIDS. 2016;5.
MLA
Broos, Katrijn, Kevin Vanderjeught, Janik Puttemans, et al. “Particle-mediated Intravenous Delivery of Antigen mRNA Results in Strong Antigen-specific T-cell Responses Despite the Induction of Type I Interferon.” MOLECULAR THERAPY-NUCLEIC ACIDS 5 (2016): n. pag. Print.
@article{8046887,
  abstract     = {Cancer vaccines based on mRNA are extensively studied. The fragile nature of mRNA has instigated research into carriers that can protect it from ribonucleases and as such enable its systemic use. However, carrier-mediated delivery of mRNA has been linked to production of type I interferon (IFN) that was reported to compromise the effectiveness of mRNA vaccines. In this study, we evaluated a cationic lipid for encapsulation of mRNA. The nanometer-sized, negatively charged lipid mRNA particles (LMPs) efficiently transfected dendritic cells and macrophages in vitro. Furthermore, i.v. delivery of LMPs resulted in rapid expression of the mRNA-encoded protein in spleen and liver, predominantly in CD11c+ cells and to a minor extent in CD11b+ cells. Intravenous immunization of mice with LMPs containing ovalbumin, human papilloma virus E7, and tyrosinase related protein-2 mRNA, either combined or separately, elicited strong antigen-specific T-cell responses. We further showed the production of type I IFNs upon i.v. LMP delivery. Although this decreased the expression of the mRNA-encoded protein, it supported the induction of antigen-specific T-cell responses. These data question the current notion that type I IFNs hamper particle-mediated mRNA vaccines.},
  articleno    = {e326},
  author       = {Broos, Katrijn and Vanderjeught, Kevin and Puttemans, Janik and Goyvaerts, Cleo and Heirman, Carlo and Dewitte, Heleen and Verbeke, Rein and Lentacker, Ine and Thielemans, Kris and Breckpot, Karine},
  issn         = {2162-2531},
  journal      = {MOLECULAR THERAPY-NUCLEIC ACIDS},
  keywords     = {particle,type I interferon,cytotoxic T lymphocyte,immunotherapy,mRNA,liposome},
  language     = {eng},
  pages        = {11},
  title        = {Particle-mediated intravenous delivery of antigen mRNA results in strong antigen-specific T-cell responses despite the induction of type I interferon},
  url          = {http://dx.doi.org/10.1038/mtna.2016.38},
  volume       = {5},
  year         = {2016},
}

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