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Augmentation of regulatory B cell activity in experimental allergic encephalomyelitis by glatiramer acetate.

ABSTRACT: We recently showed that B cells reduce CNS inflammation in mice with experimental allergic encephalomyelitis (EAE). Here, we demonstrate that adoptively transferred CD5/CD19+ B cells protect against EAE severity. Furthermore, we show that glatiramer acetate (GA), a therapeutic for relapsing multiple sclerosis treatment, amplifies this effect. Transfer of GA-conditioned B cells leads to increased production of immunoregulatory cytokines and reduced CNS inflammation, as well as decreased expression of the chemokine receptor, CXCR5, and elevated BDNF expression in the CNS. Thus B cells can protect against EAE, and GA augments this effect in maintaining immune homeostasis and controlling EAE disease progression.

SUBMITTER: Begum-Haque S

PROVIDER: S-EPMC3753076 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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Augmentation of regulatory B cell activity in experimental allergic encephalomyelitis by glatiramer acetate.

Begum-Haque Sakhina S Christy Marc M Ochoa-Reparaz Javier J Nowak Elizabeth C EC Mielcarz Daniel D Haque Azizul A Kasper Lloyd H LH

Journal of neuroimmunology 20101126 1-2

We recently showed that B cells reduce CNS inflammation in mice with experimental allergic encephalomyelitis (EAE). Here, we demonstrate that adoptively transferred CD5/CD19+ B cells protect against EAE severity. Furthermore, we show that glatiramer acetate (GA), a therapeutic for relapsing multiple sclerosis treatment, amplifies this effect. Transfer of GA-conditioned B cells leads to increased production of immunoregulatory cytokines and reduced CNS inflammation, as well as decreased expressio ...[more]

PMID: 21111489

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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.

Project description:AimsDaphnetin, a coumarin derivative extracted from Daphne odora var. marginata, has been reported to have antiinflammatory and immunosuppressive properties. Our previous study indicated that it was able to remarkably suppress the neuroinflammation and suggested its potential application in treating neuroinflammatory diseases. Multiple sclerosis (MS), a Th cell-mediated autoimmune disease, is the most common inflammatory demyelinating disease of the central nervous system (CNS). We examined whether daphnetin treatment can protect mice against experimental autoimmune encephalomyelitis (EAE), an animal model for MS.MethodsTo assess the effect of daphnetin in neuroinflammatory diseases, the EAE mice were established and treated with daphnetin at 8 mg/kg for 28 days. The severity of neuroinflammation and demyelination in the spinal cords was examined histopathologically. Infiltration of CD4(+) T cells into the CNS was assessed by immunohistochemistry, and the cytokine production was determined by ELISA. Meanwhile, the effect of daphnetin on the activity of dendritic cells (DCs) was evaluated, as assessed by DCs' capability to express surface markers, secrete cytokines, and activate naïve CD4(+) T cells. Furthermore, we explored the molecular mechanisms whereby DAPH regulated DCs' activity and thereby CD4(+) T cell responses.ResultsThe administration of daphnetin markedly alleviated the clinical symptoms of EAE and reduced the CNS inflammation and demyelination in experimental mice. Th1 and Th17 cell responses were profoundly repressed in daphnetin-treated EAE mice. Mechanistically, daphnetin treatment significantly repressed the activation, maturation, and antigen-presenting capability of DCs. NF-κB signaling was significantly reduced in daphnetin-treated DCs, along with a concomitant induction of heme oxygenase-1, a negative regulator of inflammatory signaling.ConclusionsOur findings for the first time demonstrate the property of daphnetin in regulating DCs' function and subsequently Th development. Given the low or absent toxicity associated with daphnetin, our data may suggest a novel safe and effective approach to control autoimmune neuroinflammation.

Dataset Information

Augmentation of regulatory B cell activity in experimental allergic encephalomyelitis by glatiramer acetate.

Publications

Augmentation of regulatory B cell activity in experimental allergic encephalomyelitis by glatiramer acetate.

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