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An Immunomodulatory Peptide Dendrimer Inspired from Glatiramer Acetate.

ABSTRACT: Glatiramer acetate (GA) is a random polypeptide drug used to treat multiple sclerosis (MS), a chronic autoimmune disease. With the aim of identifying a precisely defined alternative to GA, we synthesized a library of peptide dendrimers with an amino acid composition similar to GA. We then challenged the dendrimers to trigger the release of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) from human monocytes, which is one of the effects of GA on immune cells. Several of the largest dendrimers tested were as active as GA. Detailed profiling of the best hit showed that this dendrimer induces the differentiation of monocytes towards an M2 (anti-inflammatory) state as GA does, however with a distinct immune marker profile. Our peptide dendrimer might serve as starting point to develop a well-defined immunomodulatory analog of GA.

SUBMITTER: Erzina D

PROVIDER: S-EPMC9298260 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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An Immunomodulatory Peptide Dendrimer Inspired from Glatiramer Acetate.

Erzina Dina D Capecchi Alice A Javor Sacha S Reymond Jean-Louis JL

Angewandte Chemie (International ed. in English) 20211105 50

Glatiramer acetate (GA) is a random polypeptide drug used to treat multiple sclerosis (MS), a chronic autoimmune disease. With the aim of identifying a precisely defined alternative to GA, we synthesized a library of peptide dendrimers with an amino acid composition similar to GA. We then challenged the dendrimers to trigger the release of the anti-inflammatory cytokine interleukin-1 receptor antagonist (IL-1Ra) from human monocytes, which is one of the effects of GA on immune cells. Several of ...[more]

PMID: 34618395

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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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An Immunomodulatory Peptide Dendrimer Inspired from Glatiramer Acetate.

Publications

An Immunomodulatory Peptide Dendrimer Inspired from Glatiramer Acetate.

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