title: Nanoparticle-based autoantigen delivery to Treg-inducing liver sinusoidal endothelial cells enables control of autoimmunity in mice.
abstract: OBJECTIVE
  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 permanently 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. 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.
  
  
  CONCLUSIONS
  Our findings provide proof of principle that the selective delivery of autoantigen peptides to LSECs by NPs can induce antigen-specific Tregs and enable effective treatment of autoimmune disease. These findings highlight the importance of Treg induction by LSECs for immune tolerance.
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Antonella
authors.initials: A
authors.lastname: Carambia
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Freund
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Dorothee
authors.initials: D
authors.lastname: Schwinge
authors.affiliation: Department of Electron Microscopy and Micro Technology, Heinrich-Pette Institute, Hamburg, Germany.
authors.forename: Oliver T
authors.initials: OT
authors.lastname: Bruns
authors.affiliation: Institute of Physical Chemistry, University of Hamburg, Hamburg, Germany.
authors.forename: Sunhild C
authors.initials: SC
authors.lastname: Salmen
authors.affiliation: Department of Diagnostic and Interventional Radiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Harald
authors.initials: H
authors.lastname: Ittrich
authors.affiliation: Department of Electron Microscopy and Micro Technology, Heinrich-Pette Institute, Hamburg, Germany.
authors.forename: Rudolph
authors.initials: R
authors.lastname: Reimer
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Heine
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Samuel
authors.initials: S
authors.lastname: Huber
authors.affiliation: Physical Chemistry, TU Dresden, Dresden, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Waurisch
authors.affiliation: Physical Chemistry, TU Dresden, Dresden, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Eychmüller
authors.affiliation: Cellular and Molecular Medicine, University of Bristol, Bristol, UK.
authors.forename: David C
authors.initials: DC
authors.lastname: Wraith
authors.affiliation: Department of Neurology, TU München, München, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Korn
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Nielsen
authors.affiliation: Institute of Physical Chemistry, University of Hamburg, Hamburg, Germany.
authors.forename: Horst
authors.initials: H
authors.lastname: Weller
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schramm
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Lüth
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Ansgar W
authors.initials: AW
authors.lastname: Lohse
authors.affiliation: Department of Biochemistry and Molecular Cell Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Joerg
authors.initials: J
authors.lastname: Heeren
authors.affiliation: Department of Medicine I, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. Electronic address: jherkel@uke.de.
authors.forename: Johannes
authors.initials: J
authors.lastname: Herkel
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000008:administration & dosage*; D001327:Autoimmune Diseases / Q000276:immunology / Q000517:prevention & control*; D015551:Autoimmunity; D016503:Drug Delivery Systems; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000517:prevention & control; D042783:Endothelial Cells / Q000276:immunology; D008099:Liver / Q000166:cytology* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D004676:Myelin Basic Protein / Q000008:administration & dosage / Q000276:immunology; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000008:administration & dosage / Q000276:immunology; D053758:Nanoparticles / Q000008:administration & dosage; D010446:Peptide Fragments / Q000008:administration & dosage / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D001324:Autoantigens; C499047:Mbp protein, mouse; C571327:Mog protein, mouse; D004676:Myelin Basic Protein; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments
keywords: Autoimmunity; Hepatic tolerance; LSECs; Nanomedicine; Regulatory T cells