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  1. Article ; Online: Nanoparticle dose and antigen loading attenuate antigen-specific T-cell responses.

    Casey, Liam M / Decker, Joseph T / Podojil, Joseph R / Rad, Laila / Hughes, Kevin R / Rose, Justin A / Pearson, Ryan M / Miller, Stephen D / Shea, Lonnie D

    Biotechnology and bioengineering

    2022  Volume 120, Issue 1, Page(s) 284–296

    Abstract: Immune-mediated hypersensitivities such as autoimmunity, allergy, and allogeneic graft rejection are treated with therapeutics that suppress the immune system, and the lack of specificity is associated with significant side effects. The delivery of ... ...

    Abstract Immune-mediated hypersensitivities such as autoimmunity, allergy, and allogeneic graft rejection are treated with therapeutics that suppress the immune system, and the lack of specificity is associated with significant side effects. The delivery of disease-relevant antigens (Ags) by carrier systems such as poly(lactide-co-glycolide) nanoparticles (PLG-Ag) and carbodiimide (ECDI)-fixed splenocytes (SP-Ag) has demonstrated Ag-specific tolerance induction in model systems of these diseases. Despite therapeutic outcomes by both platforms, tolerance is conferred with different efficacy. This investigation evaluated Ag loading and total particle dose of PLG-Ag on Ag presentation in a coculture system of dendritic cells (DCs) and Ag-restricted T cells, with SP-Ag employed as a control. CD25 expression was observed in nearly all T cells even at low concentrations of PLG-Ag, indicating efficient presentation of Ag by dendritic cells. However, the secretion of IL-2, Th1, and Th2 cytokines (IFNγ and IL-4, respectively) varied depending on PLG-Ag concentration and Ag loading. Concentration escalation of soluble Ag resulted in an increase in IL-2 and IFNγ and a decrease in IL-4. Treatment with PLG-Ag followed a similar trend but with lower levels of IL-2 and IFNγ secreted. Transcriptional Activity CEll ARrays (TRACER) were employed to measure the real-time transcription factor (TF) activity in Ag-presenting DCs. The kinetics and magnitude of TF activity was dependent on the Ag delivery method, concentration, and Ag loading. Ag positively regulated IRF1 activity and, as carriers, NPs and ECDI-treated SP negatively regulated this signaling. The effect of Ag loading and dose on tolerance induction were corroborated in vivo using the delayed-type hypersensitivity (DTH) and experimental autoimmune encephalomyelitis (EAE) mouse models where a threshold of 8 μg/mg Ag loading and 0.5 mg PLG-Ag dose were required for tolerance. Together, the effect of Ag loading and dosing on in vitro and in vivo immune regulation provide useful insights for translating Ag-carrier systems for the clinical treatment of immune disorders.
    MeSH term(s) Animals ; Mice ; T-Lymphocytes ; Interleukin-2 ; Interleukin-4/therapeutic use ; Antigens ; Nanoparticles ; Encephalomyelitis, Autoimmune, Experimental/drug therapy
    Chemical Substances Interleukin-2 ; Interleukin-4 (207137-56-2) ; Antigens
    Language English
    Publishing date 2022-10-21
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 280318-5
    ISSN 1097-0290 ; 0006-3592
    ISSN (online) 1097-0290
    ISSN 0006-3592
    DOI 10.1002/bit.28252
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Cargo-less nanoparticles program innate immune cell responses to toll-like receptor activation.

    Casey, Liam M / Kakade, Sandeep / Decker, Joseph T / Rose, Justin A / Deans, Kyle / Shea, Lonnie D / Pearson, Ryan M

    Biomaterials

    2019  Volume 218, Page(s) 119333

    Abstract: Developing biomaterials to control the responsiveness of innate immune cells represents a clinically relevant approach to treat diseases with an underlying inflammatory basis, such as sepsis. Sepsis can involve activation of Toll-like receptor (TLR) ... ...

    Abstract Developing biomaterials to control the responsiveness of innate immune cells represents a clinically relevant approach to treat diseases with an underlying inflammatory basis, such as sepsis. Sepsis can involve activation of Toll-like receptor (TLR) signaling, which activates numerous inflammatory pathways. The breadth of this inflammation has limited the efficacy of pharmacological interventions that target a single molecular pathway. Here, we developed cargo-less particles as a single-agent, multi-target platform to elicit broad anti-inflammatory action against innate immune cells challenged by multiple TLR agonists. The particles, prepared from poly(lactic-co-glycolic acid) (PLGA) and poly(lactic acid) (PLA), displayed potent molecular weight-, polymer composition-, and charge-dependent immunomodulatory properties, including downregulation of TLR-induced costimulatory molecule expression and cytokine secretion. Particles prepared using the anionic surfactant poly(ethylene-alt-maleic acid) (PEMA) significantly blunted the responses of antigen presenting cells to TLR4 (lipopolysaccharide) and TLR9 (CpG-ODN) agonists, demonstrating broad inhibitory activity to both extracellular and intracellular TLR ligands. Interestingly, particles prepared using poly(vinyl alcohol) (PVA), a neutrally-charged surfactant, only marginally inhibited inflammatory cytokine secretions. The biochemical pathways modulated by particles were investigated using TRanscriptional Activity CEll aRrays (TRACER), which implicated IRF1, STAT1, and AP-1 in the mechanism of action for PLA-PEMA particles. Using an LPS-induced endotoxemia mouse model, administration of PLA-PEMA particles prior to or following a lethal challenge resulted in significantly improved mean survival. Cargo-less particles affect multiple biological pathways involved in the development of inflammatory responses by innate immune cells and represent a potentially promising therapeutic strategy to treat severe inflammation.
    MeSH term(s) Animals ; Endotoxemia/immunology ; Endotoxemia/metabolism ; Enzyme-Linked Immunosorbent Assay ; Female ; Flow Cytometry ; Immunity, Innate/genetics ; Immunity, Innate/physiology ; Inflammation/immunology ; Inflammation/metabolism ; Mice ; Mice, Inbred C57BL ; Nanoparticles/chemistry ; Polyesters/chemistry ; Polylactic Acid-Polyglycolic Acid Copolymer/chemistry ; RAW 264.7 Cells ; Sepsis/immunology ; Sepsis/metabolism ; Toll-Like Receptors/metabolism
    Chemical Substances Polyesters ; Toll-Like Receptors ; Polylactic Acid-Polyglycolic Acid Copolymer (1SIA8062RS) ; poly(lactide) (459TN2L5F5)
    Language English
    Publishing date 2019-07-04
    Publishing country Netherlands
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 603079-8
    ISSN 1878-5905 ; 0142-9612
    ISSN (online) 1878-5905
    ISSN 0142-9612
    DOI 10.1016/j.biomaterials.2019.119333
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article: Cargo-less nanoparticles program innate immune cell responses to toll-like receptor activation

    Casey, Liam M / Kakade, Sandeep / Decker, Joseph T / Rose, Justin A / Deans, Kyle / Shea, Lonnie D / Pearson, Ryan M

    Biomaterials. 2019 Oct., v. 218

    2019  

    Abstract: Developing biomaterials to control the responsiveness of innate immune cells represents a clinically relevant approach to treat diseases with an underlying inflammatory basis, such as sepsis. Sepsis can involve activation of Toll-like receptor (TLR) ... ...

    Abstract Developing biomaterials to control the responsiveness of innate immune cells represents a clinically relevant approach to treat diseases with an underlying inflammatory basis, such as sepsis. Sepsis can involve activation of Toll-like receptor (TLR) signaling, which activates numerous inflammatory pathways. The breadth of this inflammation has limited the efficacy of pharmacological interventions that target a single molecular pathway. Here, we developed cargo-less particles as a single-agent, multi-target platform to elicit broad anti-inflammatory action against innate immune cells challenged by multiple TLR agonists. The particles, prepared from poly(lactic-co-glycolic acid) (PLGA) and poly(lactic acid) (PLA), displayed potent molecular weight-, polymer composition-, and charge-dependent immunomodulatory properties, including downregulation of TLR-induced costimulatory molecule expression and cytokine secretion. Particles prepared using the anionic surfactant poly(ethylene-alt-maleic acid) (PEMA) significantly blunted the responses of antigen presenting cells to TLR4 (lipopolysaccharide) and TLR9 (CpG-ODN) agonists, demonstrating broad inhibitory activity to both extracellular and intracellular TLR ligands. Interestingly, particles prepared using poly(vinyl alcohol) (PVA), a neutrally-charged surfactant, only marginally inhibited inflammatory cytokine secretions. The biochemical pathways modulated by particles were investigated using TRanscriptional Activity CEll aRrays (TRACER), which implicated IRF1, STAT1, and AP-1 in the mechanism of action for PLA-PEMA particles. Using an LPS-induced endotoxemia mouse model, administration of PLA-PEMA particles prior to or following a lethal challenge resulted in significantly improved mean survival. Cargo-less particles affect multiple biological pathways involved in the development of inflammatory responses by innate immune cells and represent a potentially promising therapeutic strategy to treat severe inflammation.
    Keywords Toll-like receptor 4 ; Toll-like receptor 9 ; agonists ; animal models ; anionic surfactants ; anti-inflammatory activity ; antigen-presenting cells ; biochemical pathways ; biocompatible materials ; cytokines ; endotoxemia ; immunomodulators ; inflammation ; ligands ; lipopolysaccharides ; mechanism of action ; mice ; molecular weight ; nanoparticles ; oligodeoxyribonucleotides ; polylactic acid ; polyvinyl alcohol ; secretion ; sepsis (infection) ; therapeutics ; transcription (genetics)
    Language English
    Dates of publication 2019-10
    Publishing place Elsevier Ltd
    Document type Article
    ZDB-ID 603079-8
    ISSN 0142-9612
    ISSN 0142-9612
    DOI 10.1016/j.biomaterials.2019.119333
    Database NAL-Catalogue (AGRICOLA)

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  4. Article ; Online: Conjugation of Transforming Growth Factor Beta to Antigen-Loaded Poly(lactide- co-glycolide) Nanoparticles Enhances Efficiency of Antigen-Specific Tolerance.

    Casey, Liam M / Pearson, Ryan M / Hughes, Kevin R / Liu, Jeffrey M H / Rose, Justin A / North, Madeleine G / Wang, Leon Z / Lei, Mei / Miller, Stephen D / Shea, Lonnie D

    Bioconjugate chemistry

    2017  Volume 29, Issue 3, Page(s) 813–823

    Abstract: Current strategies for treating autoimmunity involve the administration of broad-acting immunosuppressive agents that impair healthy immunity. Intravenous (i.v.) administration of poly(lactide- co-glycolide) nanoparticles (NPs) containing disease- ... ...

    Abstract Current strategies for treating autoimmunity involve the administration of broad-acting immunosuppressive agents that impair healthy immunity. Intravenous (i.v.) administration of poly(lactide- co-glycolide) nanoparticles (NPs) containing disease-relevant antigens (Ag-NPs) have demonstrated antigen (Ag)-specific immune tolerance in models of autoimmunity. However, subcutaneous (s.c.) delivery of Ag-NPs has not been effective. This investigation tested the hypothesis that codelivery of the immunomodulatory cytokine, transforming growth factor beta 1 (TGF-β), on Ag-NPs would modulate the immune response to Ag-NPs and improve the efficiency of tolerance induction. TGF-β was coupled to the surface of Ag-NPs such that the loadings of Ag and TGF-β were independently tunable. The particles demonstrated bioactive delivery of Ag and TGF-β in vitro by reducing the inflammatory phenotype of bone marrow-derived dendritic cells and inducing regulatory T cells in a coculture system. Using an in vivo mouse model for multiple sclerosis, experimental autoimmune encephalomyelitis, TGF-β codelivery on Ag-NPs resulted in improved efficacy at lower doses by i.v. administration and significantly reduced disease severity by s.c. administration. This study demonstrates that the codelivery of immunomodulatory cytokines on Ag-NPs may enhance the efficacy of Ag-specific tolerance therapies by programming Ag presenting cells for more efficient tolerance induction.
    MeSH term(s) Animals ; Antigens/administration & dosage ; Antigens/chemistry ; Antigens/therapeutic use ; Cells, Cultured ; Encephalomyelitis, Autoimmune, Experimental/drug therapy ; Encephalomyelitis, Autoimmune, Experimental/immunology ; Female ; Immune Tolerance/drug effects ; Immunologic Factors/administration & dosage ; Immunologic Factors/chemistry ; Immunologic Factors/therapeutic use ; Mice ; Mice, Inbred C57BL ; Multiple Sclerosis/drug therapy ; Multiple Sclerosis/immunology ; Nanoconjugates/administration & dosage ; Nanoconjugates/chemistry ; Nanoconjugates/therapeutic use ; Polyglactin 910/administration & dosage ; Polyglactin 910/chemistry ; Polyglactin 910/therapeutic use ; Transforming Growth Factor beta/administration & dosage ; Transforming Growth Factor beta/chemistry ; Transforming Growth Factor beta/therapeutic use
    Chemical Substances Antigens ; Immunologic Factors ; Nanoconjugates ; Transforming Growth Factor beta ; Polyglactin 910 (34346-01-5)
    Language English
    Publishing date 2017-11-30
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 1024041-x
    ISSN 1520-4812 ; 1043-1802
    ISSN (online) 1520-4812
    ISSN 1043-1802
    DOI 10.1021/acs.bioconjchem.7b00624
    Database MEDical Literature Analysis and Retrieval System OnLINE

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