Nanoparticle-based autoantigen delivery to Treg-inducing liver sinusoidal endothelial cells enables control of autoimmunity in mice

Antonella Carambia, Barbara Freund, Dorothee Schwinge, Oliver T. Bruns, Sunhild C. Salmen, Harald Ittrich, Rudolph Reimer, Markus Heine, Samuel Huber, Christian Waurisch, Alexander Eychmüller, David C. Wraith, Thomas Korn, Peter Nielsen, Horst Weller, Christoph Schramm, Stefan Lüth, Ansgar W. Lohse, Joerg Heeren, Johannes Herkel*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

71 Citations (Scopus)

Abstract

BACKGROUND & AIMS: It is well known that the liver can induce immune tolerance, yet this knowledge could thus far not be translated into effective treatments for autoimmune diseases. We have previously shown that liver sinusoidal endothelial cells (LSECs) could substantially contribute to hepatic tolerance through their ability to induce CD4+ Foxp3+ regulatory T cells (Tregs). Here, we explored whether the Treg-inducing potential of LSECs could be harnessed for the treatment of autoimmune disease.

METHODS: We engineered a polymeric nanoparticle (NP) carrier for the selective delivery of autoantigen peptides to LSECs in vivo. In the well-characterized autoimmune disease model of experimental autoimmune encephalomyelitis (EAE), we investigated whether administration of LSEC-targeting autoantigen peptide-loaded NPs could protect mice from autoimmune disease.

RESULTS: We demonstrate that NP-based autoantigen delivery to LSECs could completely and lastingly prevent the onset of clinical EAE. More importantly, in a therapeutic approach, mice with already established EAE improved rapidly and substantially following administration of a single dose of autoantigen peptide-loaded NPs, whereas the control group deteriorated. Treatment efficacy seemed to depend on Tregs, because the Treg frequencies in the spleens of mice treated with autoantigen peptide-loaded NPs were significantly higher than those in vehicle-treated mice. Moreover, NP-mediated disease control was abrogated after Treg-depletion by repeated administration of Treg-depleting antibody.

CONCLUSION: Our findings provide proof-of-principle that the selective delivery of autoantigen peptides to LSECs by nanoparticles can induce antigen-specific Tregs and enable effective treatment of autoimmune disease. These findings underscore the importance of Treg-induction by LSECs for immune tolerance.

Original languageEnglish
Article number5508
Pages (from-to)1349-1356
Number of pages8
JournalJournal of Hepatology
Volume62
Issue number6
Early online date21 Jan 2015
DOIs
Publication statusPublished - 1 Jun 2015

Bibliographical note

Copyright © 2015. Published by Elsevier B.V.

Keywords

  • Autoimmunity
  • Hepatic tolerance
  • LSECs
  • Nanomedicine
  • Regulatory T cells

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