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Immunoregulation of Theiler's virus-induced demyelinating disease by glatiramer acetate without suppression of antiviral immune responses.

ABSTRACT: While most disease-modifying drugs (DMDs) regulate multiple sclerosis (MS) by suppressing inflammation, they can potentially suppress antiviral immunity, causing progressive multifocal leukoencephalopathy (PML). The DMD glatiramer acetate (GA) has been used for MS patients who are at high risk of PML. We investigated whether GA is safe for use in viral infections by using a model of MS induced by infection with Theiler's murine encephalomyelitis virus (TMEV). Treatment of TMEV-infected mice with GA neither enhanced viral loads nor suppressed antiviral immune responses, while it resulted in an increase in the Foxp3/Il17a ratio and IL-4/IL-10 production. This is the first study to suggest that GA could be safe for MS patients with a proven viral infection.

SUBMITTER: Omura S

PROVIDER: S-EPMC6276114 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Immunoregulation of Theiler's virus-induced demyelinating disease by glatiramer acetate without suppression of antiviral immune responses.

Omura Seiichi S Sato Fumitaka F Martinez Nicholas E NE Range Tierra T Ekshyyan Lesya L Minagar Alireza A Alexander J Steven JS Tsunoda Ikuo I

Archives of virology 20180123 5

While most disease-modifying drugs (DMDs) regulate multiple sclerosis (MS) by suppressing inflammation, they can potentially suppress antiviral immunity, causing progressive multifocal leukoencephalopathy (PML). The DMD glatiramer acetate (GA) has been used for MS patients who are at high risk of PML. We investigated whether GA is safe for use in viral infections by using a model of MS induced by infection with Theiler's murine encephalomyelitis virus (TMEV). Treatment of TMEV-infected mice with ...[more]

PMID: 29362931

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Project description:The outbreak of the COVID-19 pandemic in China has become an urgent health and economic challenge. There is a current race for developing strategies to treat and/or prevent COVID-19 worldwide. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the strain of coronavirus that causes COVID-19. The aim of the present work was to evaluate the efficacy of the combined complex (nano-conjugates) of two FDA-approved drugs, sitagliptin (SIT) and glatiramer acetate (GA), against a human isolate of the SARS-CoV-2 virus. SIT-GA nano-conjugates were prepared according to a full three-factor bilevel (23) factorial design. The SIT concentration (mM, X1), GA concentration (mM, X2), and pH (X3) were selected as the factors. The particle size (nm, Y1) and zeta potential (mV, Y2) were assessed as responses. Characterization of the optimized formula for the Fourier-transform infrared (FTIR) spectroscopy and transmission electron microscopy (TEM) was carried out. In addition, the half-maximal inhibitory concentration (IC50) in Vero-E6 epithelial cells previously infected with the virus was investigated. The results revealed that the optimized formula of the prepared complex was a 1:1 SIT:GA molar ratio at a pH of 10, which met the required criteria with a desirability value of 0.878 and had a particle size and zeta potential at values of 77.42 nm and 27.67 V, respectively. The SIT-GA nano-complex showed antiviral potential against an isolate of SARS-CoV-2 with IC50 values of 16.14, 14.09, and 8.52 µM for SIT, GA, and SIT-GA nano-conjugates, respectively. Molecular docking has shown that the formula's components have a high binding affinity to the COVID 3CL protease, essential for coronavirus replication, paralleled by 3CL protease inhibition (IC50 = 2.87 µM). An optimized formulation of SIT-GA could guarantee both enhanced deliveries to target cells and improved cellular uptake. Further clinical studies are being carried out to validate the clinical efficacy of the optimized formulation against SARS-CoV-2.

Project description:Background: Glatiramer acetate (GA) is a well-established treatment option for patients with clinically isolated syndrome and relapsing-remitting multiple sclerosis (MS) with few side effects. The double transgenic mouse model spontaneous opticospinal encephalomyelitis (OSE), based on recombinant myelin oligodendrocyte glycoprotein35-55 reactive T and B cells, mimicks features of chronic inflammation and degeneration in MS and related disorders. Here, we investigated the effects of prophylactic GA treatment on the clinical course, histological alterations and peripheral immune cells in OSE. Objective: To investigate the effects of prophylactic glatiramer acetate (GA) treatment in a mouse model of spontaneous opticospinal encephalomyelitis (OSE). Methods: OSE mice with a postnatal age of 21 to 28 days without signs of encephalomyelitis were treated once daily either with 150 µg GA or vehicle intraperitoneally (i. p.). The animals were scored daily regarding clinical signs and weight. The animals were sacrificed after 30 days of treatment or after having reached a score of 7.0 due to animal care guidelines. We performed immunohistochemistry of spinal cord sections and flow cytometry analysis of immune cells. Results: Preventive treatment with 150 µg GA i. p. once daily significantly reduced clinical disease progression with a mean score of 3.9 ± 1.0 compared to 6.2 ± 0.7 in control animals (p < 0.01) after 30 d in accordance with positive effects on weight (p < 0.001). The immunohistochemistry showed that general inflammation, demyelination or CD11c+ dendritic cell infiltration did not differ. There was, however, a modest reduction of the Iba1+ area (p < 0.05) and F4/80+ area upon GA treatment (p < 0.05). The immune cell composition of secondary lymphoid organs showed a trend towards an upregulation of regulatory T cells, which lacked significance. Conclusions: Preventive treatment with GA reduces disease progression in OSE in line with modest effects on microglia/macrophages. Due to the lack of established prophylactic treatment options for chronic autoimmune diseases with a high risk of disability, our study could provide valuable indications for translational medicine.

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Immunoregulation of Theiler's virus-induced demyelinating disease by glatiramer acetate without suppression of antiviral immune responses.

Publications

Immunoregulation of Theiler's virus-induced demyelinating disease by glatiramer acetate without suppression of antiviral immune responses.

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