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Microparticles bearing encephalitogenic peptides induce T-cell tolerance and ameliorate experimental autoimmune encephalomyelitis

A Corrigendum to this article was published on 10 June 2013

This article has been updated

Abstract

Aberrant T-cell activation underlies many autoimmune disorders, yet most attempts to induce T-cell tolerance have failed. Building on previous strategies for tolerance induction that exploited natural mechanisms for clearing apoptotic debris, we show that antigen-decorated microparticles (500-nm diameter) induce long-term T-cell tolerance in mice with relapsing experimental autoimmune encephalomyelitis. Specifically, intravenous infusion of either polystyrene or biodegradable poly(lactide-co-glycolide) microparticles bearing encephalitogenic peptides prevents the onset and modifies the course of the disease. These beneficial effects require microparticle uptake by marginal zone macrophages expressing the scavenger receptor MARCO and are mediated in part by the activity of regulatory T cells, abortive T-cell activation and T-cell anergy. Together these data highlight the potential for using microparticles to target natural apoptotic clearance pathways to inactivate pathogenic T cells and halt the disease process in autoimmunity.

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Figure 1: Antigen-coupled polystyrene microparticles are effective for inducing tolerance for the prevention and treatment of EAE.
Figure 2: MARCO has a crucial role in tolerance induction using antigen-coupled microparticles.
Figure 3: Response of antigen-specific T cells to tolerance induction with Ag-PSB.
Figure 4: Antigen-specific T cells undergo suboptimal proliferation in response to Ag-PSB.
Figure 5: Antigen-specific T cells are abortively activated after Ag-PSB encounter but do not synthesize IL-17A and IFN-γ after direct in vivo exposure to Ag-PSB or after subsequent immunogenic stimulation.
Figure 6: Short-term tolerance induced by i.v. treatment with Ag-PSB is caused primarily by anergy induction.

Change history

  • 04 June 2013

    In the version of this article initially published, the description of mice in the first paragraph of Online Methods was incomplete. Female SJL/J mice should have been described as SJL/JCrHsD; female BALB/c mice, as BALB/cJ mice; TCR transgenic mice expressing a TCR on the SJL/J background, expressed it on the SJL/JCrHsD background. Marco−/− mice, described as “on the BALB/c background,” should have been described as backcrossed to the BALB/cAncr1 (Charles River) background. The errors have been corrected in the HTML and PDF versions of the article.

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Acknowledgements

This work was supported by a grant from the Myelin Repair Foundation, US National Institutes of Health grants NS026543 and EB013198, Juvenile Diabetes Research Foundation grant 17-2011-343 and the Australian National Health and Medical Research Council grants 512413 and 1030897. We also thank V. Kuchroo and L. Kobchik of Harvard University for providing transgenic mice.

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D.R.G. and A.J.M. designed and performed the majority of the experiments, interpreted results and assisted with manuscript preparation. D.P.M., R.L.T., Z.N.H., W.T.Y. and M.T.G. performed and/or assisted with several experiments. X.L. provided reagents and advice. S.D.M. provided intellectual input, secured the funding and guided experimental design and the preparation of the manuscript with major input from M.P., N.J.C.K. and L.D.S.

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Correspondence to Nicholas JC King, Lonnie D Shea or Stephen D Miller.

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Getts, D., Martin, A., McCarthy, D. et al. Microparticles bearing encephalitogenic peptides induce T-cell tolerance and ameliorate experimental autoimmune encephalomyelitis. Nat Biotechnol 30, 1217–1224 (2012). https://doi.org/10.1038/nbt.2434

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