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

JOURNAL OF HEPATOLOGY

卷:62

Article

Carambia, Antonella¹  Freund, Barbara²  Schwinge, Dorothee¹  Bruns, Oliver T.³  Salmen, Sunhild C.⁴  Ittrich, Harald⁵  Reimer, Rudolph³  Heine, Markus²  Huber, Samuel¹  Waurisch, Christian⁶  Eychmueller, Alexander⁶  Wraith, David C.⁷  Korn, Thomas⁸  Nielsen, Peter²  Weller, Horst⁴  Schramm, Christoph¹  Lueth, Stefan¹  Lohse, Ansgar W.¹  Heeren, Joerg²  Herkel, Johannes¹ 

[1] Univ Med Ctr Hamburg Eppendorf, Dept Med 1, D-20246 Hamburg, Germany

[2] Univ Med Ctr Hamburg Eppendorf, Dept Biochem & Mol Cell Biol, D-20246 Hamburg, Germany

[3] Heinrich Pette Inst, Dept Electron Microscopy & Micro Technol, Hamburg, Germany

[4] Univ Hamburg, Inst Phys Chem, Hamburg, Germany

[5] Univ Med Ctr Hamburg Eppendorf, Dept Diagnost & Intervent Radiol, D-20246 Hamburg, Germany

[6] Tech Univ Dresden, Phys Chem, Dresden, Germany

[7] Univ Bristol, Cellular & Mol Med, Bristol, Avon, England

[8] Tech Univ Munich, Dept Neurol, Munich, Germany

关键词: LSECs;    Hepatic tolerance;    Autoimmunity;    Regulatory T cells;    Nanomedicine;   

DOI  :  10.1016/j.jhep.2015.01.006

来源: Elsevier

【 摘 要 】

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 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 peptideloaded 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. Conclusion: 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. (C) 2015 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

【 授权许可】

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