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Targeting interferon activity to dendritic cells enables in vivo tolerization and protection against EAE in mice

Anje Cauwels (UGent) , Sandra Van Lint (UGent) , Dominiek Catteeuw (UGent) , Shengru Pang, Franciane Paul, Elke Rogge (UGent) , Annick Verhee (UGent) , Marco Prinz, Niko Kley, Gilles Uzé, et al.
(2019) JOURNAL OF AUTOIMMUNITY. 97. p.70-76
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Abstract
Type I Interferon (IFN) is widely used for multiple sclerosis (MS) treatment, but its side effects are limiting and its mechanism of action still unknown. Furthermore, 30-50% of MS patients are unresponsive, and IFN can even induce relapses. Fundamental understanding of the cellular target(s) of IFN will help to optimize treatments by reducing side effects and separating beneficial from detrimental effects. To improve clinical systemic IFN usage, we are developing AcTaferons (Activity-on-Target IFNs = AFNs), optimized IFN-based immunocytokines that allow cell-specific targeting. In experimental autoimmune encephalitis (EAE) in mice, high dose WT mIFN alpha could delay disease, but caused mortality and severe hematological deficits. In contrast, AFN targeted to dendritic cells (DC, via Clec9A) protected without mortality or hematological consequences. Conversely, CD8-targeted AFN did not protect and exacerbated weight loss, indicating the presence of both protective and unfavorable IFN effects in EAE. Comparing Clec9A-, XCR1-and SiglecH-targeting, we found that targeting AFN to plasmacytoid (p) and conventional (c) DC is superior and non-toxic compared to WT mIFN. DC-targeted AFN increased pDC numbers and their tolerogenic potential, evidenced by increased TGF beta and IDO synthesis and regulatory T cell induction. In addition, both regulatory T and B cells produced significantly more immunosuppressive TGF beta and IL-10. In conclusion, specific DC-targeting of IFN activity induces a robust in vivo tolerization, efficiently protecting against EAE, without noticeable side effects. Thus, dissecting positive and negative IFN effects via cell-specific targeting may result in better and safer MS therapy and response rates.
Keywords
EAE, Interferon, AcTaferon, Dendritic cells, Tolerization, MULTIPLE-SCLEROSIS, IMMUNE REGULATION, BETA, CTLA-4, DC, ACTIVATION, GENERATION, RELEVANCE, PROMOTES, EFFICACY

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MLA
Cauwels, Anje, et al. “Targeting Interferon Activity to Dendritic Cells Enables in Vivo Tolerization and Protection against EAE in Mice.” JOURNAL OF AUTOIMMUNITY, vol. 97, 2019, pp. 70–76, doi:10.1016/j.jaut.2018.10.010.
APA
Cauwels, A., Van Lint, S., Catteeuw, D., Pang, S., Paul, F., Rogge, E., … Tavernier, J. (2019). Targeting interferon activity to dendritic cells enables in vivo tolerization and protection against EAE in mice. JOURNAL OF AUTOIMMUNITY, 97, 70–76. https://doi.org/10.1016/j.jaut.2018.10.010
Chicago author-date
Cauwels, Anje, Sandra Van Lint, Dominiek Catteeuw, Shengru Pang, Franciane Paul, Elke Rogge, Annick Verhee, et al. 2019. “Targeting Interferon Activity to Dendritic Cells Enables in Vivo Tolerization and Protection against EAE in Mice.” JOURNAL OF AUTOIMMUNITY 97: 70–76. https://doi.org/10.1016/j.jaut.2018.10.010.
Chicago author-date (all authors)
Cauwels, Anje, Sandra Van Lint, Dominiek Catteeuw, Shengru Pang, Franciane Paul, Elke Rogge, Annick Verhee, Marco Prinz, Niko Kley, Gilles Uzé, and Jan Tavernier. 2019. “Targeting Interferon Activity to Dendritic Cells Enables in Vivo Tolerization and Protection against EAE in Mice.” JOURNAL OF AUTOIMMUNITY 97: 70–76. doi:10.1016/j.jaut.2018.10.010.
Vancouver
1.
Cauwels A, Van Lint S, Catteeuw D, Pang S, Paul F, Rogge E, et al. Targeting interferon activity to dendritic cells enables in vivo tolerization and protection against EAE in mice. JOURNAL OF AUTOIMMUNITY. 2019;97:70–6.
IEEE
[1]
A. Cauwels et al., “Targeting interferon activity to dendritic cells enables in vivo tolerization and protection against EAE in mice,” JOURNAL OF AUTOIMMUNITY, vol. 97, pp. 70–76, 2019.
@article{8583437,
  abstract     = {{Type I Interferon (IFN) is widely used for multiple sclerosis (MS) treatment, but its side effects are limiting and its mechanism of action still unknown. Furthermore, 30-50% of MS patients are unresponsive, and IFN can even induce relapses. Fundamental understanding of the cellular target(s) of IFN will help to optimize treatments by reducing side effects and separating beneficial from detrimental effects. To improve clinical systemic IFN usage, we are developing AcTaferons (Activity-on-Target IFNs = AFNs), optimized IFN-based immunocytokines that allow cell-specific targeting. 
In experimental autoimmune encephalitis (EAE) in mice, high dose WT mIFN alpha could delay disease, but caused mortality and severe hematological deficits. In contrast, AFN targeted to dendritic cells (DC, via Clec9A) protected without mortality or hematological consequences. Conversely, CD8-targeted AFN did not protect and exacerbated weight loss, indicating the presence of both protective and unfavorable IFN effects in EAE. Comparing Clec9A-, XCR1-and SiglecH-targeting, we found that targeting AFN to plasmacytoid (p) and conventional (c) DC is superior and non-toxic compared to WT mIFN. DC-targeted AFN increased pDC numbers and their tolerogenic potential, evidenced by increased TGF beta and IDO synthesis and regulatory T cell induction. In addition, both regulatory T and B cells produced significantly more immunosuppressive TGF beta and IL-10. 
In conclusion, specific DC-targeting of IFN activity induces a robust in vivo tolerization, efficiently protecting against EAE, without noticeable side effects. Thus, dissecting positive and negative IFN effects via cell-specific targeting may result in better and safer MS therapy and response rates.}},
  author       = {{Cauwels, Anje and Van Lint, Sandra and Catteeuw, Dominiek and Pang, Shengru and Paul, Franciane and Rogge, Elke and Verhee, Annick and Prinz, Marco and Kley, Niko and Uzé, Gilles and Tavernier, Jan}},
  issn         = {{0896-8411}},
  journal      = {{JOURNAL OF AUTOIMMUNITY}},
  keywords     = {{EAE,Interferon,AcTaferon,Dendritic cells,Tolerization,MULTIPLE-SCLEROSIS,IMMUNE REGULATION,BETA,CTLA-4,DC,ACTIVATION,GENERATION,RELEVANCE,PROMOTES,EFFICACY}},
  language     = {{eng}},
  pages        = {{70--76}},
  title        = {{Targeting interferon activity to dendritic cells enables in vivo tolerization and protection against EAE in mice}},
  url          = {{http://doi.org/10.1016/j.jaut.2018.10.010}},
  volume       = {{97}},
  year         = {{2019}},
}
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