Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs
Stefan Lüth, … , Johannes Herkel, Ansgar W. Lohse
Stefan Lüth, … , Johannes Herkel, Ansgar W. Lohse
Published September 18, 2008
Citation Information: J Clin Invest. 2008;118(10):3403-3410. https://doi.org/10.1172/JCI32132.
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Research Article

Ectopic expression of neural autoantigen in mouse liver suppresses experimental autoimmune neuroinflammation by inducing antigen-specific Tregs

Abstract

Tregs are important mediators of immune tolerance to self antigens, and it has been suggested that Treg inactivation may cause autoimmune disease. Therefore, immunotherapy approaches that aim to restore or expand autoantigen-specific Treg activity might be beneficial for the treatment of autoimmune disease. Here we report that Treg-mediated suppression of autoimmune disease can be achieved in vivo by taking advantage of the ability of the liver to promote immune tolerance. Expression of the neural autoantigen myelin basic protein (MBP) in the liver was accomplished stably in liver-specific MBP transgenic mice and transiently using gene transfer to liver cells in vivo. Such ectopic MBP expression induced protection from autoimmune neuroinflammation in a mouse model of multiple sclerosis. Protection from autoimmunity was mediated by MBP-specific CD4+CD25+Foxp3+ Tregs, as demonstrated by the ability of these cells to prevent disease when adoptively transferred into nontransgenic mice and to suppress conventional CD4+CD25– T cell proliferation after antigen-specific stimulation with MBP in vitro. The generation of MBP-specific CD4+CD25+Foxp3+ Tregs in vivo depended on expression of MBP in the liver, but not in skin, and occurred by TGF-β–dependent peripheral conversion from conventional non-Tregs. Our findings indicate that autoantigen expression in the liver may generate autoantigen-specific Tregs. Thus, targeting of autoantigens to hepatocytes may be a novel approach to prevention or treatment of autoimmune diseases.

Authors

Stefan Lüth, Samuel Huber, Christoph Schramm, Thorsten Buch, Stefan Zander, Christine Stadelmann, Wolfgang Brück, David C. Wraith, Johannes Herkel, Ansgar W. Lohse

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Figure 1

Ectopic expression of MBP in liver induces suppression of EAE.

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Ectopic expression of MBP in liver induces suppression of EAE. (A) CRP-M...
(A) CRP-MBP mice expressed transgenic MBP specifically in the liver (L) and weakly in the thymus (T), but not in other organs, such as kidney (K) and heart (H). (B) K5-MBP mice expressed transgenic MBP specifically in the skin (S) and in the thymus, but not in liver or kidney. (C) CRP-MBP mice (n = 24) and nontransgenic littermates (n = 25) were immunized with Ac1–9 to induce EAE. Data are mean ± SEM from 3 independent experiments. (D) Brain histology at day 18 of EAE showed dense perivascular and subpial inflammatory infiltrates in nontransgenic mice, but not in CRP-MBP mice. Staining with H&E or immunostaining for macrophages (anti-Mac3) or T cells (anti-CD3) is shown. Scale bar: 200 μm. (E) K5-MBP mice (n = 11) and nontransgenic littermates (n = 10) were immunized with Ac1–9 to induce EAE. Data are mean ± SEM from 2 independent experiments. (F) Transient hepatic MBP expression facilitated by hydrodynamics-based gene transfer with MBP-encoding vector (n = 10), but not by empty control vector (n = 8), suppressed EAE. Data are mean ± SEM. (G) Transient hepatic MBP expression facilitated by adenoviral gene transfer of MBP (n = 10), but not by control adenovirus (lacZ; n = 10), suppressed EAE. Data are mean ± SEM.