Z Gastroenterol 2015; 53 - A5_3
DOI: 10.1055/s-0034-1397207

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

A Carambia 1, B Freund 2, D Schwinge 1, OT Bruns 3, SC Salmen 4, H Ittrich 5, R Reimer 3, M Heine 2, S Huber 1, C Waurisch 6, A Eychmüller 6, DC Wraith 7, T Korn 8, P Nielsen 2, H Weller 4, C Schramm 1, S Lüth 1, AW Lohse 1, J Heeren 2, J Herkel 1
  • 1University Hospital Hamburg-Eppendorf, Department of Medicine I, Hamburg, Germany
  • 2University Hospital Hamburg-Eppendorf, Department of Biochemistry and Molecular Cell Biology, Hamburg, Germany
  • 3Heinrich-Pette Institute, Hamburg, Germany
  • 4Universität Hamburg, Institute of Physical Chemistry, Hamburg, Germany
  • 5University Hospital Hamburg-Eppendorf, Department of Diagnostic and Interventional Radiology, Hamburg, Germany
  • 6Technische Universität Dresden, Physical Chemistry, Dresden, Germany
  • 7University of Bristol, Cellular and Molecular Medicine, Bristol, UK
  • 8Technische Universität München, Department of Neurology, Munich, Germany

Background/Aims: Previously, we have shown that ectopic expression of a neural autoantigen in the liver induced the generation of autoantigen-specific CD4+ Foxp3+ regulatory T cells (Tregs) that could suppress experimental autoimmune neuroinflammation (Lüth S et al., J Clin Invest. 2008). Moreover, we identified liver sinusoidal endothelial cells (LSECs) as the major antigen-presenting cell type responsible for hepatic Treg induction (Carambia A et al., J Hepatol. 2014). Here we aimed to explore whether targeted delivery of autoantigen-peptides to LSECs could be harnessed for the induction of autoantigen-specific Tregs in vivo and the treatment of autoimmune disease.

Methods: We engineered a polymeric nanoparticle carrier (NP) that facilitates efficient 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: In two independent disease models, we studied whether treatment with LSEC-targeting myelin-peptide-loaded nanoparticles could protect mice from Myelin Basic Protein (MBP)-induced EAE in B10.PL mice or from Myelin Oligodendrocyte Glycoprotein (MOG)-induced EAE in C57Bl/6 mice. Intriguingly, in both disease models, a single intravenous injection of MBP or MOG peptide-loaded nanoparticles one day after EAE-induction provoked a lasting and complete protection from clinical EAE; in contrast, control mice treated with PBS or with unloaded nanoparticles developed clinical EAE symptoms, including hind-limb paralysis. Even more importantly, the mean clinical score of mice with already established EAE (mean score of 1.6) improved rapidly and substantially following administration of a single dose of MOG-loaded nanoparticles (mean change in EAE score -0.6), whereas the control group deteriorated (mean change in EAE score +1.0; P= 0.0002). Treatment efficacy depended on Tregs since the Treg frequencies in the spleens of mice treated with MOG peptide loaded nanoparticles were significantly higher than those in PBS-treated mice (12.0% vs. 6.8% Foxp3+ of CD4+; P= 0.001). Moreover, nanoparticle-mediated disease control was abrogated after Treg-depletion by repeated administration of the Treg-depleting PC61 antibody (mean score at disease maximum: 0.6 vs. 2.3; P= 0.0027). Mechanistically, NP-induced Tregs seemed to prevent the egress of inflammatory effector cells from the spleens of MOG-NP recipients, as indicated by increased splenocyte numbers and down-regulation of CXCR4 and Syndecan-4 compared to PBS-treated control mice.

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.

Corresponding author: Carambia, Antonella

E-Mail: a.carambia@uke.de