Specific immunotherapy of experimental myasthenia gravis in vitro and in vivo: The Guided Missile strategy

Sun, W.; Adams, Roger; Miagkov, Alexei; Lu, Y.; Juon, H.-S.; Drachman, Daniel B.

doi:10.1016/j.jneuroim.2012.06.007

Cited by 5 publications

(3 citation statements)

References 70 publications

(62 reference statements)

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“… 83 Finally, the tolerizing function of DCs can be exploited even to induce specific killing of AChR-targeted effector T-cells, as in the “Guided Missile” strategy in which genetically engineered DCs simultaneously target and eliminate the individual’s unique AChR-specific T-cell repertoire, by presenting AChR epitopes and expressing Fas ligand. 84 Eventually, very recent data indicate that aside from the classical cell therapy, a tolerizing effect can be obtained in EAMG also via the delivery of exosomes produced by immature DCs. 85 …”

Section: Eamg Models For the Investigation Of Therapeutic Approachesmentioning

confidence: 99%

Animal models of myasthenia gravis: utility and limitations

Mantegazza

Cordiglieri

Consonni

et al. 2016

IJGM

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Myasthenia gravis (MG) is a chronic autoimmune disease caused by the immune attack of the neuromuscular junction. Antibodies directed against the acetylcholine receptor (AChR) induce receptor degradation, complement cascade activation, and postsynaptic membrane destruction, resulting in functional reduction in AChR availability. Besides anti-AChR antibodies, other autoantibodies are known to play pathogenic roles in MG. The experimental autoimmune MG (EAMG) models have been of great help over the years in understanding the pathophysiological role of specific autoantibodies and T helper lymphocytes and in suggesting new therapies for prevention and modulation of the ongoing disease. EAMG can be induced in mice and rats of susceptible strains that show clinical symptoms mimicking the human disease. EAMG models are helpful for studying both the muscle and the immune compartments to evaluate new treatment perspectives. In this review, we concentrate on recent findings on EAMG models, focusing on their utility and limitations.

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Section: Eamg Models For the Investigation Of Therapeutic Approachesmentioning

confidence: 99%

Animal models of myasthenia gravis: utility and limitations

Mantegazza

Cordiglieri

Consonni

et al. 2016

IJGM

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“…Killer antigen-presenting cells (KAPCs) thus have been developed by genetically engineered to express the Fas ligand (FasL) onto B cell lines (4), dendritic cells (DCs) (5) or macrophages (6) to induce peripheral antigen-specific apoptosis of T cells (7–14). Although the promising results in the treatment of chronic infections (15, 16), allograft rejection (8, 10, 17), or autoimmune diseases (9) in murine or human models, cell-based FasL-expressing KAPCs still suffer from several significant problems related to their cellular nature: the risk of infection, tumorigenicity or immunogenicity raised by live cells, the time consuming, and cost-intensive generation when scaled, large batch-to-batch variability of FasL expression (18), mature killer DCs may highly express B7.1 or B7.2 and weakly express FasL (19), thereby eliciting vigorous T cell responses toward other antigens and massive neutrophil infiltration (20), and the sensitivity to their in vivo and in vitro environments due to the activity of cytotoxic T cells, which can lead to KAPC depletion or unwanted changes in cell-cell signaling (21). …”

Section: Introductionmentioning

confidence: 99%

An Antigen-Presenting and Apoptosis-Inducing Polymer Microparticle Prolongs Alloskin Graft Survival by Selectively and Markedly Depleting Alloreactive CD8+ T Cells

Wang

Shahzad

et al. 2017

Front. Immunol.

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Selectively depleting the pathogenic T cells is a fundamental strategy for the treatment of allograft rejection and autoimmune disease since it retains the overall immune function of host. The concept of killer artificial antigen-presenting cells (KaAPCs) has been developed by co-coupling peptide–major histocompatibility complex (pMHC) multimer and anti-Fas monoclonal antibody (mAb) onto the polymeric microparticles (MPs) to induce the apoptosis of antigen-specific T cells. But little information is available about its in vivo therapeutic potential and mechanism. In this study, polyethylenimine (PEI)-coated poly lactic-co-glycolic acid microparticle (PLGA MP) was fabricated as a cell-sized scaffold to covalently co-couple H-2Kb-Ig dimer and anti-Fas mAb for the generation of alloantigen-presenting and apoptosis-inducing MPs. Intravenous infusions of the biodegradable KaAPCs prolonged the alloskin graft survival for 43 days in a single MHC-mismatched murine model, depleted the most of H-2Kb-alloreactive CD8+ T cells in peripheral blood, spleen, and alloskin graft in an antigen-specific manner and anti-Fas-dependent fashion. The cell-sized KaAPCs circulated throughout vasculature into liver, kidney, spleen, lymph nodes, lung, and heart, but few ones into local allograft at early stage, with a retention time up to 36 h in vivo. They colocalized with CD8+ T cells in secondary lymphoid organs while few ones contacted with CD4+ T cells, B cells, macrophage, and dendritic cells, or internalized by phagocytes. Importantly, the KaAPC treatment did not significantly impair the native T cell repertoire or non-pathogenic immune cells, did not obviously suppress the overall immune function of host, and did not lead to visible organ toxicity. Our results strongly document the high potential of PLGA MP-based KaAPCs as a novel antigen-specific immunotherapy for allograft rejection and autoimmune disorder. The in vivo mechanism of alloinhibition, tissue distribution, and biosafety were also initially characterized, which will facilitate its translational studies from bench to bedside.

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“…One proposed treatment is based on the use of FasL-transfected dendritic cells (DCs) or monocytes to induce peripheral antigen-specific apoptosis of T cells, which are referred to as killer antigen-presenting cells (KAPCs) [ 6 - 8 ]. Despite promising results in the treatment of chronic infections [ 9 , 10 ], allograft rejection [ 11 ], or autoimmune diseases [ 12 ], the cell-based KAPCs still suffer from several principal drawbacks: they are time-consuming and cost-intensive when generated on a large scale, and there is batch-to-batch variability in FasL expression. In addition, mature KAPCs may display strong expression of CD86 or 4-1BBL and weak expression of FasL, thereby eliciting vigorous T cell responses towards other antigens and massive neutrophil infiltration [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

A biodegradable killer microparticle to selectively deplete antigen-specific T cells in vitro and in vivo

Wang

Fang

et al. 2016

Oncotarget

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The specific eradication of pathogenic T cells for the treatment of allograft rejections and autoimmune disorders without impairment of overall immune function is a fundamental goal. Here, cell-sized poly(lactic-co-glycolic acid) microparticles (PLGA MPs) were prepared as a scaffold to co-display the peptide/major histocompatibility complex (pMHC, target antigen) and anti-Fas monoclonal antibody (apoptosis-inducing molecule) for the generation of biodegradable killer MPs. Ovalbumin (OVA) antigen-targeted killer MPs significantly depleted OVA-specific CD8+ T cells in an antigen-specific manner, both in vitro and in OT-1 mice. After intravenous administration, the killer MPs predominantly accumulated in the liver, lungs, and gut of OT-1 mice with a retention time of up to 48 hours. The killing effects exerted by killer MPs persisted for 4 days after two injections. Moreover, the H-2Kb alloantigen-targeted killer MPs were able to eliminate low-frequency alloreactive T cells and prolong alloskin graft survival for 41.5 days in bm1 mice. Our data indicate that PLGA-based killer MPs are capable of specifically depleting pathogenic T cells, which highlights their therapeutic potential for treating allograft rejection and autoimmune disorders.

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Specific immunotherapy of experimental myasthenia gravis in vitro and in vivo: The Guided Missile strategy

Cited by 5 publications

References 70 publications

Animal models of myasthenia gravis: utility and limitations

Animal models of myasthenia gravis: utility and limitations

An Antigen-Presenting and Apoptosis-Inducing Polymer Microparticle Prolongs Alloskin Graft Survival by Selectively and Markedly Depleting Alloreactive CD8+ T Cells

A biodegradable killer microparticle to selectively deplete antigen-specific T cells in vitro and in vivo

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