Administration methods and dosage of poly(lactic acid)-glycol intervention to myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalitis mice.

BACKGROUND: Myelin oligodendrocyte glycoprotein-associated disorders (MOGAD) is an autoimmune central nervous system disease. Antigen-specific immune tolerance using nanoparticles such as Polylactic-co-glycolic acid (PLGA) have recently been used as a new therapeutic tolerization approach for CNS autoimmune diseases. We examined whether MOG1-125 conjugated with PLGA could induce MOG-specific immune tolerance in an experimental autoimmune encephalitis (EAE) mouse model. EAE was induced in sixty C57BL/6 J wild-type mice using MOG1-125 peptide with complete Freund's Adjuvant. The mice were divided into 12 groups (n = 5 each) to test the ability of MOG1-125 conjugated PLGA intervention to mitigate the severity or improve the outcomes from EAE with and without rapamycin compared to antigen alone or PLGA alone. EAE score and serum MOG-IgG titers were compared among the interventions.Kindly check and confirm the processed Affiliation “4” is appropriate.I confirmed the Aff 4.Affiliation: Corresponding author information have been changed to present affiliation. Kindly check and confirm.I checked and confirmed the Corresponding author's information. RESULTS: Mice with EAE that were injected intraperitoneally with MOG1-125 conjugated PLGA + rapamycin complex showed dose-dependent mitigation of EAE score. Intraperitoneal and intravenous administration resulted in similar clinical outcomes, whereas 80% of mice treated with subcutaneous injection had a recurrence of clinical score worsening after approximately 1 week. Although there was no significant difference in EAE scores between unconjugated-PLGA and MOG-conjugated PLGA, serum MOG-IgG tended to decrease in the MOG-conjugated PLGA group compared to controls. CONCLUSION: Intraperitoneal administration of PLGA resulted in dose-dependent and longer-lasting immune tolerance than subcutaneous administration. The induction of immune tolerance using PLGA may represent a future therapeutic option for patients with MOGAD.

Gold nanoparticles and polyethylene glycol alleviate clinical symptoms and alter cytokine secretion in a mouse model of experimental autoimmune encephalomyelitis.

Gold nanoparticles (GNPs) are attractive nanoparticles with unique electronic and optical properties in the nanotechnology field and are widely used in various biomedical fields. Studies have shown that these particles also exhibit antioxidant and anti-inflammatory properties. On the other hand, polyethylene glycol (PEG) that used to stabilize GNPs also exhibits antioxidant and anti-inflammatory properties due to their membrane resealing properties. The aim of this study was to evaluate the ameliorative effect of GNPs and PEG in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). EAE was induced in female C57BL/6 mice with injection of an emulsion of myelin oligodendrocyte glycoprotein (MOG35-55) peptide and Freund's adjuvant. GNPs measuring 25 nm were prepared, and their size was determined using transmission electron microscopy (TEM), then intraperitoneal injection of GNPs and PEG (MW 1500; 30% w/v) was initiated after immunization and continued until the day 27 postimmunization (13 injections in total). The EAE clinical scores and body weights were evaluated. We analyzed cental nervous system's cell infiltration and demyelinated lesions using hematoxylin and eosin and luxol fast blue staining, respectively. Also, interleukin-23 and interleukin-27 were examined using the ELISA technique. The severity of MS symptoms was significantly decreased in the treated groups with GNPs and PEG. Histological examination of the spinal cord showed that the number and severity of cells' infiltration and demyelinated lesions decreased significantly, and also the cytokine levels of IL-23 and IL-27 altered in treated groups. These results show that GNPs and PEG ameliorate the clinical course of EAE in mice. Our findings demonstrate proof of principle for potential of GNPs and PEG as novel agents for therapeutic approaches in the alleviated clinical symptoms of MS. © 2019 IUBMB Life, 71(9):1313-1321, 2019.

Designing drug-free biodegradable nanoparticles to modulate inflammatory monocytes and neutrophils for ameliorating inflammation.

Inflammation associated with autoimmune diseases and chronic injury is an initiating event that leads to tissue degeneration and dysfunction. Inflammatory monocytes and neutrophils systemically circulate and enter inflamed tissue, and pharmaceutical based targeting of these cells has not substantially improved outcomes and has had side effects. Herein, we investigated the design of drug-free biodegradable nanoparticles, notably without any active pharmaceutical ingredient or targeting ligand, that target circulating inflammatory monocytes and neutrophils in the vasculature to inhibit them from migrating into inflamed tissue. Nanoparticles were formed from 50:50 poly(DL-lactide-co-glycolide) (PLG) with two molecular weights (Low, High) and poly(DL-lactide) (PLA) (termed PLG-L, PLG-H, and PDLA, respectively) and were analyzed for their association with monocytes and neutrophils and their impact on disease course along with immune cell trafficking. For particles injected intravenously for 6 consecutive days to mice with experimental autoimmune encephalomyelitis (EAE), PLG-H particles had significantly lower EAE clinical scores than PBS control, while PLG-L and PDLA particles had modest or negligible effect on EAE onset. In vivo and in vitro data suggests that PLG-H particles had high association with immune cells, with preferential association with blood neutrophils relative to other particles. PLG-H particles restrained immune cells from the central nervous system (CNS), with increased accumulation in the spleen, which was not observed for mice receiving PDLA or control treatments. These results demonstrate that the particle composition influences the association with inflammatory monocytes and neutrophils in the vasculature, with the potential to redirect trafficking and ameliorate inflammation.

Fabrication principles and their contribution to the superior in vivo therapeutic efficacy of nano-liposomes remote loaded with glucocorticoids.

We report here the design, development and performance of a novel formulation of liposome- encapsulated glucocorticoids (GCs). A highly efficient (>90%) and stable GC encapsulation was obtained based on a transmembrane calcium acetate gradient driving the active accumulation of an amphipathic weak acid GC pro-drug into the intraliposome aqueous compartment, where it forms a GC-calcium precipitate. We demonstrate fabrication principles that derive from the physicochemical properties of the GC and the liposomal lipids, which play a crucial role in GC release rate and kinetics. These principles allow fabrication of formulations that exhibit either a fast, second-order (t(1/2) ~1 h), or a slow, zero-order release rate (t(1/2) ~ 50 h) kinetics. A high therapeutic efficacy was found in murine models of experimental autoimmune encephalomyelitis (EAE) and hematological malignancies.

[Primary study of the recombinant immunotoxin DT390-mRantes in EAE therapy].

AIM: To construct a novel eukaryotic expression plasmid including the recombinant immunotoxin DT390-mRantes and treat experimental autoimmune encephalomyelitis (EAE) in mice. METHODS: EAE in C57BL/6 mice were induced by the extracted MBP. The mRantes fragment was inserted into the eukaryotic expression plasmid SRalpha containing DT390. Then cationic liposome-embedded plasmid DNA was injected into the muscles of the hind-limbs in mice. The effect of DT390-mRantes was evaluated by observing clinical symptoms, pathological changes of brain, relative cytokine of peripheral blood, and the proportion of T cells and B cells. RESULTS: The recombinant immunotoxin DT390-mRantes was successfully constructed. Compared the mice in treated group with those in untreated group the clinical symptoms of EAE were alleviated, the infiltration of inflammatory cells were decreased, the IFN-gamma level was fallen, and the ratio of T/B cells was decreased. CONCLUSION: The recombinant immunotoxin DT390-mRantes has distinct effects on EAE in mice, which may be used for beneficial reference to the therapy of MS.