Article

Nanoparticle-mediated codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis

Center for Neurologic Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115.
Proceedings of the National Academy of Sciences (Impact Factor: 9.81). 06/2012; 109(28):11270-5. DOI: 10.1073/pnas.1120611109
Source: PubMed

ABSTRACT The immune response is normally controlled by regulatory T cells (Tregs). However, Treg deficits are found in autoimmune diseases, and therefore the induction of functional Tregs is considered a potential therapeutic approach for autoimmune disorders. The activation of the ligand-activated transcription factor aryl hydrocarbon receptor by 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) or other ligands induces dendritic cells (DCs) that promote FoxP3(+) Treg differentiation. Here we report the use of nanoparticles (NPs) to coadminister ITE and a T-cell epitope from myelin oligodendrocyte glycoprotein (MOG)(35)(-55) to promote the generation of Tregs by DCs. NP-treated DCs displayed a tolerogenic phenotype and promoted the differentiation of Tregs in vitro. Moreover, NPs carrying ITE and MOG(35-55) expanded the FoxP3(+) Treg compartment and suppressed the development of experimental autoimmune encephalomyelitis, an experimental model of multiple sclerosis. Thus, NPs are potential new tools to induce functional Tregs in autoimmune disorders.

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Available from: Francisco J Quintana, Aug 31, 2015
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    • "Additionally, granulocyte macrophage colony stimulating factor (GM-CSF) is another pleiotropic cytokine impacting a number of immune cells, particularly APCs. Granulocyte macrophage colony stimulating factor is secreted by peripheral tissues under pathologic conditions and influences DC recruitment, phagocytic activity, antigen presentation capacity and proliferation [45]. Further, Gaudreau et al. demonstrated that GM-CSF treated semi-mature DCs play an integral role in prevention of T1D in NOD mice and further, suggest that they induce IL-10 secreting CD4+ CD25+ Tregs that suppress diabetogenic T cells that promote diabetes development [30] [31]. "
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    ABSTRACT: We developed a novel poly(lactic-co-glycolic acid)-based, microparticle (MP) system providing concurrent delivery of multiple encapsulated immuno-suppressive factors and antigen, for in vivo conditioning of dendritic cells (DCs) toward a tolerance promoting pathway. Subcutaneous administration prevents onset of type 1 diabetes (T1D) in NOD mice. Two MP sizes were made: phagocytosable MPs were fabricated encapsulating vitamin D3 or insulin B(9-23) peptide, while unphagocytosable MPs were fabricated encapsulating TGF-β1 or GM-CSF. The combination of Vit D3/TGF-β1 MPs confers an immature and LPS activation-resistant phenotype to DCs, and MP-delivered antigen is efficiently and functionally presented. Notably, two subcutaneous injections into 4week old NOD mice using the combination of MPs encapsulating Vit D3, Ins B, TGF-β1 and GM-CSF protected 40% of mice from T1D development, significant in comparison to the control. This work represents one of the first applications of a biomaterial-based, MP vaccine system to successfully prevent autoimmune diabetes. Copyright © 2015. Published by Elsevier Inc.
    Clinical Immunology 04/2015; DOI:10.1016/j.clim.2015.03.023 · 3.99 Impact Factor
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    • "In summary, the induction of Tregs in vivo by treatment with AhR ligands represents a new therapeutic approach for treatment of immune-mediated diseases. Tregs can be induced by targeting the AhR directly in CD4+ T cells [4], or indirectly via AhR activation in tolerogenic dendritic cells [42], [43]. Our data show that 10-Cl-BBQ directly targets CD4+ T cells to induce AhR-dependent Tregs while simultaneously suppressing murine GVHD without overt toxicity. "
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    PLoS ONE 02/2014; 9(2):e88726. DOI:10.1371/journal.pone.0088726 · 3.23 Impact Factor
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    • "The endogenous Ahr ligand, ITE, attenuates EAE symptoms by promoting Tregs expansion and inducing tolerogenic DCs that are capable of promoting the Tregs differentiation [89]. Similar results are observed when EAE mice are treated with nanoparticles carrying ITE and MOG35–55 [127]. Conversely, treating mice with FICZ or indoxyl 3-sulfate (I3S) worsens EAE, which is likely attributed to the prompted Th17 differentiation [13, 128]. "
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