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: 9.67). 06/2012; 109(28):11270-5. DOI: 10.1073/pnas.1120611109
Source: PubMed


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
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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.
    Full-text · Article · Apr 2015 · Clinical Immunology
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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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    ABSTRACT: The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that plays multiple roles in regulation of immune and inflammatory responses. The ability of certain AhR ligands to induce regulatory T cells (Tregs) has generated interest in developing AhR ligands for therapeutic treatment of immune-mediated diseases. To this end, we designed a screen for novel Treg-inducing compounds based on our understanding of the mechanisms of Treg induction by the well-characterized immunosuppressive AhR ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). We screened a ChemBridge small molecule library and identified 10-chloro-7H-benzimidazo[2,1-a]benzo[de]Iso-quinolin-7-one (10-Cl-BBQ) as a potent AhR ligand that was rapidly metabolized and not cytotoxic to proliferating T cells. Like TCDD,10-Cl-BBQ altered donor CD4(+) T cell differentiation during the early stages of a graft versus host (GVH) response resulting in expression of high levels of CD25, CTLA-4 and ICOS, as well as several genes associated with Treg function. The Treg phenotype required AhR expression in the donor CD4(+) T cells. Foxp3 was not expressed in the AhR-induced Tregs implicating AhR as an independent transcription factor for Treg induction. Structure-activity studies showed that unsubstituted BBQ as well as 4, 11-dichloro-BBQ were capable of inducing AhR-Tregs. Other substitutions reduced activation of AhR. Daily treatment with 10-Cl-BBQ during the GVH response prevented development of GVH disease in an AhR-dependent manner with no overt toxicity. Together, our data provide strong support for development of select BBQs that activate the AhR to induce Tregs for treatment of immune-mediated diseases.
    Full-text · Article · Feb 2014 · PLoS ONE
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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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    ABSTRACT: The immune system is regulated by distinct signaling pathways that control the development and function of the immune cells. Accumulating evidence suggest that ligation of aryl hydrocarbon receptor (Ahr), an environmentally responsive transcription factor, results in multiple cross talks that are capable of modulating these pathways and their downstream responsive genes. Most of the immune cells respond to such modulation, and many inflammatory response-related genes contain multiple xenobiotic-responsive elements (XREs) boxes upstream. Active research efforts have investigated the physiological role of Ahr in inflammation and autoimmunity using different animal models. Recently formed paradigm has shown that activation of Ahr by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) or 3,3'-diindolylmethane (DIM) prompts the differentiation of CD4(+)Foxp3(+) regulatory T cells (Tregs) and inhibits T helper (Th)-17 suggesting that Ahr is an innovative therapeutic strategy for autoimmune inflammation. These promising findings generate a basis for future clinical practices in humans. This review addresses the current knowledge on the role of Ahr in different immune cell compartments, with a particular focus on inflammation and autoimmunity.
    Full-text · Article · Jan 2014
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