Glatiramer acetate reduces lymphocyte proliferation and enhances IL-5 and IL-13 production through modulation of monocyte-derived dendritic cells in multiple sclerosis

Sanna, Alessandra; Fois, Maria Laura; Arru, Giannina; Huang, Yu‐Min; Link, Hans; Pugliatti, Maura; Rosati, Giulio; Sotgiu, Stefano

doi:10.1111/j.1365-2249.2006.02997.x

Cited by 51 publications

(34 citation statements)

References 20 publications

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“…It is possible that IL-5 plays a protective role in MS because the levels are increased during treatment with IFN-b and, especially, with glatiramer acetate. [39][40][41] The production of IL-5 by some of the patients with high cytokine responses to MBP may therefore reflect a protective, compensatory mechanism, but further studies with a larger number of patients are required to clarify this.…”

Section: Cd4mentioning

confidence: 99%

T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis

et al. 2008

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SummaryAutoreactive T cells are thought to play an essential role in the pathogenesis of multiple sclerosis (MS). We examined the stimulatory effect of human myelin basic protein (MBP) on mononuclear cell (MNC) cultures from 22 patients with MS and 22 sex-matched and age-matched healthy individuals, and related the patient responses to disease activity, as indicated by magnetic resonance imaging. The MBP induced a dose-dependent release of interferon-c (IFN-c), tumour necrosis factor-a (TNF-a) and interleukin-10 (IL-10) by patient-derived MNCs. The patients' cells produced higher amounts of IFN-c and TNF-a, and lower amounts of IL-10, than cells from healthy controls (P < 0Á03 to P < 0Á04). Five patients with MS and no controls, displayed MBP-induced CD4 + T-cell proliferation. These high-responders exhibited enhanced production of IL-17, IFN-c, IL-5 and IL-4 upon challenge with MBP, as compared with the remaining patients and the healthy controls (P < 0Á002 to P < 0Á01). A strong correlation was found between the MBP-induced CD4 + T-cell proliferation and production of IL-17, IFN-c, IL-5 and IL-4 (P < 0Á0001 to P < 0Á01) within the patient group, and the production of IL-17 and IL-5 correlated with the number of active plaques on magnetic resonance images (P = 0Á04 and P = 0Á007). These data suggest that autoantigendriven CD4 + T-cell proliferation and release of IL-17 and IL-5 may be associated with disease activity. Larger studies are needed to confirm this.

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Section: Cd4mentioning

confidence: 99%

T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis

et al. 2008

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“…To overcome this deleterious effect, T cells that cross-react weakly with autoantigens without Several studies have demonstrated a significant effect of Cop-1 on the innate cells of the immune system, such as macrophages, DC, and monocytes [53][54][55][56]. Recent studies have characterized the phenotypes of these cells from Cop-1-treated patients [54,57].…”

Section: Discussionmentioning

confidence: 99%

T cell independent mechanism for copolymer‐1‐induced neuroprotection

et al. 2007

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Despite active investigation of copolymer-1 (Cop-1) for nearly 40 years the mechanisms underlying its neuroprotective properties remain contentious. Nonetheless, current dogma for Cop-1 neuroprotective activities in autoimmune and neurodegenerative diseases include bystander suppression of autoimmune T cells and attenuation of microglial responses. In this report, we demonstrate that Cop-1 interacts directly with primary human neurons and decreases neuronal cell death induced by staurosporine or oxidative stress. This neuroprotection is mediated through protein kinase Ca and brainderived neurotrophic factor. Dendritic cells (DC) uptake Cop-1, deliver it to the injury site, and release it in an active form. Interactions between Cop-1 and DC enhance DC blood brain barrier migration. In a rat model with optic nerve crush injury, Cop-1-primed DC induce T cell independent neuroprotection. These findings may facilitate the development of neuroprotective approaches using DC-mediated Cop-1 delivery to diseased nervous tissue. IntroductionCopolymer-1 (Cop-1) was developed to mimic the encephalitogenic epitope of myelin basic protein (MBP). However, when administered in complete Freund's adjuvant it failed to induce experimental autoimmune encephalitis (EAE). Surprisingly, Cop-1 suppressed EAE when administered with MBP [1][2][3][4]. These observations led to the development of Cop-1 as a treatment for relapsing-remitting multiple sclerosis [5][6][7][8]. Over the past three decades, scientists have tried to determine how Cop-1 exerts its therapeutic effects [2,4,9,10]. Cop-1-specific T cells partially cross-react with MBP, leading to the secretion of neurotrophic and antiinflammatory factors such as brain derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor, [11][12][13]. [17], and experimentally induced encephalitis [18]. The mechanism(s) underlying Cop-1-induced neuroprotection were attributed to T cells. T cells modulate microglial and astrocyte responses and as such attenuate toxic inflammatory activities and neurodegeneration [11,12,19]. Indeed, the mechanism underlying T cellinduced neuroprotection is linked to modulation of microglial function [20] and increased production of neurotrophins at the site of injury [11,12]. After central nervous system (CNS) injury microglia commonly display a neurotoxic phenotype with local production of glutamate and increased expression of nitric oxide synthase (iNOS), pro-inflammatory cytokines, quinolinic acid and arachidonic acid and its metabolites [21,22]. T cells can induce a neuroprotective microglial phenotype [20].Under certain conditions with progressive neurodegeneration the Cop-1 neuroprotective response is seen before an adaptive immune response is generated [15,17,23], suggesting that Cop-1 induced neuroprotection may be, at least in part, T cell independent. We now demonstrate that Cop-1 treatment of primary human neurons intoxicated with staurosporine or reactiveoxygen species significantly decreases cell death. This neuroprotection is associ...

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“…Furthermore, our findings indicate that inflammatory events like those in the MS plaques, where DCs mature in the perivascular space leading to the expansion of T cells, also occur in NLGM and NLWM. Both glatiramer acetate and interferon β were able to suppress DC function in relapsing remitting MS (Hussien et al, 2001;Sanna et al, 2006;Schreiner et al, 2004) suggesting that DC-targeted therapies could be beneficial in autoimmune demyelination. Thus, targeting DCs and DC-T cell interactions represents a possible new therapeutic approach in MS.…”

Section: Discussionmentioning

confidence: 99%

Dendritic cells are abundant in non-lesional gray matter in multiple sclerosis

Cudrici

Ito

Zafranskaia

et al. 2007

Experimental and Molecular Pathology

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We have analyzed the localization of dendritic cells (DCs) in non-lesional gray matter (NLGM) in comparison to non-lesional white matter (NLWM) and acute or chronic active multiple sclerosis (MS) lesions. Immunohistochemistry was performed on cryostat sections for DCs markers (CD209, CD205, CD83) and other markers for inflammatory cells (CD68, CD8, CD4, CD3, CCR7, CCR5). We found cells expressing CD209 and containing myelin basic protein in both perivascular and parenchymal areas of NLGM. Our findings showing the expression of CD209 + cells in NLGM parenchymal areas are surprising relative to the previous literature which reported the presence of CD209 + DCs only in MS plaque perivascular areas. Although less numerous than CD209 + cells, NLGM cells expressing mature DCs marker CD205 were consistently detected in perivascular cuffs of most lesions. In double labeling experiments, some but not all of the CD209 + cells also expressed CD68 and CCR5. We also found CD209 + cells in close contact with CD3 + lymphocytes suggesting that DCs might contribute to the local activation of pathogenic T cells in the NLGM. Since injury to the NLGM is one of the key factors associated with disability accumulation, targeting DCs may represent a possible new therapeutic approach in MS to prevent disease progression.

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Glatiramer acetate reduces lymphocyte proliferation and enhances IL-5 and IL-13 production through modulation of monocyte-derived dendritic cells in multiple sclerosis

Cited by 51 publications

References 20 publications

T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis

T helper cell type 1 (Th1), Th2 and Th17 responses to myelin basic protein and disease activity in multiple sclerosis

T cell independent mechanism for copolymer‐1‐induced neuroprotection

Dendritic cells are abundant in non-lesional gray matter in multiple sclerosis

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