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ABSTRACT: Transcriptomic and proteomic analyses of multiple sclerosis (MS) lesions indicate alterations in the gamma-aminobutyric acid (GABA) inhibitory system, suggesting its involvement in the disease process. To further elucidate the role of GABA in central nervous system (CNS) inflammation in vivo, the chronic myelin oligodendrocyte glycoprotein (MOG)(35-55) experimental autoimmune encephalomyelitis (EAE) model was used. Daily GABA injections (200mg/kg) from day 3 onwards significantly augmented disease severity, which was associated with increased CNS mRNA expression levels of tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6. GABA-treated mice showed enhanced MOG-dependent proliferation and were skewed towards a T helper 1 phenotype. Moreover, in vitro, the lipopolysaccharide (LPS)-induced increase in interleukin (IL)-6 production by macrophages was enhanced at low GABA concentrations (0.03-0.3mM). In sharp contrast to exogenous GABA administration, endogenous GABA increment by systemic treatment with the GABA-transaminase inhibitor vigabatrin (250mg/kg) had prophylactic as well as therapeutic potential in EAE. Together, these results indicate an immune amplifying role of GABA in neuroinflammatory diseases like MS.
Journal of neuroimmunology 11/2012; · 2.84 Impact Factor
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ABSTRACT: Aging of the immune system contributes to the increased morbidity and mortality of the elderly population and may occur prematurely in patients with immune disorders. One of the main characteristics of immunosenescence is the expansion of CD4(+)CD28(-) T cells in the blood. These cells are effector memory T cells with cytotoxic capacity, and have been recently described to have pathogenic potential in a variety of immune disorders. Interestingly, CD4(+)CD28(-) T cells have now been found to infiltrate target tissues of patients with multiple sclerosis, rheumatoid arthritis, myopathies, acute coronary syndromes, and other immune-related diseases. In this review, we discuss potential factors and mechanisms that may induce the expansion of these cells, as well as their putative pathogenic mechanisms in immune disorders.
Trends in Molecular Medicine 07/2012; 18(8):446-53. · 10.35 Impact Factor
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Jeroen F J Bogie,
Silke Timmermans,
Vân Anh Huynh-Thu,
Alexandre Irrthum,
Hubert J M Smeets,
Jan-Åke Gustafsson,
Knut R Steffensen,
Monique Mulder,
Piet Stinissen, Niels Hellings,
Jerome J A Hendriks
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ABSTRACT: Multiple sclerosis is a chronic, inflammatory, demyelinating disease of the central nervous system in which macrophages and microglia play a central role. Foamy macrophages and microglia, containing degenerated myelin, are abundantly found in active multiple sclerosis lesions. Recent studies have described an altered macrophage phenotype after myelin internalization. However, it is unclear by which mechanisms myelin affects the phenotype of macrophages and how this phenotype can influence lesion progression. Here we demonstrate, by using genome wide gene expression analysis, that myelin-phagocytosing macrophages have an enhanced expression of genes involved in migration, phagocytosis and inflammation. Interestingly, myelin internalization also induced the expression of genes involved in liver-X-receptor signaling and cholesterol efflux. In vitro validation shows that myelin-phagocytosing macrophages indeed have an increased capacity to dispose intracellular cholesterol. In addition, myelin suppresses the secretion of the pro-inflammatory mediator IL-6 by macrophages, which was mediated by activation of liver-X-receptor β. Our data show that myelin modulates the phenotype of macrophages by nuclear receptor activation, which may subsequently affect lesion progression in demyelinating diseases such as multiple sclerosis.
PLoS ONE 01/2012; 7(9):e44998. · 4.09 Impact Factor
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Annelies Vanheel,
Ruth Daniels,
Stéphane Plaisance,
Kurt Baeten,
Jerome J A Hendriks,
Pierre Leprince,
Debora Dumont,
Johan Robben,
Bert Brône,
Piet Stinissen,
Jean-Paul Noben, Niels Hellings
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ABSTRACT: A more detailed insight into disease mechanisms of multiple sclerosis (MS) is crucial for the development of new and more effective therapies. MS is a chronic inflammatory autoimmune disease of the central nervous system. The aim of this study is to identify novel disease associated proteins involved in the development of inflammatory brain lesions, to help unravel underlying disease processes. Brainstem proteins were obtained from rats with MBP induced acute experimental autoimmune encephalomyelitis (EAE), a well characterized disease model of MS. Samples were collected at different time points: just before onset of symptoms, at the top of the disease and following recovery. To analyze changes in the brainstem proteome during the disease course, a quantitative proteomics study was performed using two-dimensional difference in-gel electrophoresis (2D-DIGE) followed by mass spectrometry. We identified 75 unique proteins in 92 spots with a significant abundance difference between the experimental groups. To find disease-related networks, these regulated proteins were mapped to existing biological networks by Ingenuity Pathway Analysis (IPA). The analysis revealed that 70% of these proteins have been described to take part in neurological disease. Furthermore, some focus networks were created by IPA. These networks suggest an integrated regulation of the identified proteins with the addition of some putative regulators. Post-synaptic density protein 95 (DLG4), a key player in neuronal signalling and calcium-activated potassium channel alpha 1 (KCNMA1), involved in neurotransmitter release, are 2 putative regulators connecting 64% of the identified proteins. Functional blocking of the KCNMA1 in macrophages was able to alter myelin phagocytosis, a disease mechanism highly involved in EAE and MS pathology. Quantitative analysis of differentially expressed brainstem proteins in an animal model of MS is a first step to identify disease-associated proteins and networks that warrant further research to study their actual contribution to disease pathology.
PLoS ONE 01/2012; 7(4):e35544. · 4.09 Impact Factor
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Bieke Broux,
Kim Pannemans,
Xin Zhang,
Silva Markovic-Plese,
Tom Broekmans,
Bert O Eijnde,
Bart Van Wijmeersch,
Veerle Somers,
Piet Geusens,
Susanne van der Pol,
Jack van Horssen,
Piet Stinissen, Niels Hellings
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ABSTRACT: Immunosenescence, or ageing of the immune system, contributes to the increased morbidity and mortality seen in the elderly population. Premature immunosenescence is shown to occur in a subgroup of patients with autoimmune diseases. One of the main characteristics of immunosenescence is the expansion of CD4(+)CD28(-) T cells in the blood. In this study, we investigate the potential contribution of these cells to disease processes in a subgroup of multiple sclerosis (MS) and rheumatoid arthritis (RA) patients. Characterization of CD4(+)CD28(-) T cells in patients and healthy controls reveals that they have an inflammation-seeking effector-memory T cell phenotype with cytotoxic properties, as they expel cytotoxic granules in response to a polyclonal stimulus or MS-related autoantigens. We identify CX(3)CR1, the fractalkine receptor, as a selective marker to discriminate CD4(+)CD28(-) T cells from their CD4(+)CD28(+) counterparts. CX(3)CR1 expression enables CD4(+)CD28(-) T cells to migrate towards a fractalkine gradient in vitro. In addition, we find increased levels of fractalkine in the cerebrospinal fluid and inflammatory lesions of MS patients. We demonstrate for the first time that CD4(+)CD28(-) T cells accumulate in MS lesions of a subgroup of patients. Moreover, we have indications that these cells are cytotoxic in the target tissue. Overall, our findings suggest that CD4(+)CD28(-) T cells migrate in response to a chemotactic gradient of fractalkine to sites of inflammation, where they contribute to the inflammatory processes in a subgroup of patients with MS and RA.
Journal of Autoimmunity 11/2011; 38(1):10-9. · 7.37 Impact Factor
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ABSTRACT: The inhibitory neurotransmitter glycine is known to enhance microglial nitric oxide production. However, up to now, the mechanism is undocumented. Since calcium is an important second messenger in both immune and glial cells, we studied the effects of glycine on intracellular calcium signaling. We found that millimolar concentrations of glycine enhance microglial intracellular calcium transients induced by 100 μM ATP or by 500 nM thapsigargin. This modulation was unaffected by the glycine receptor antagonist strychnine and could not be mimicked by glycine receptor agonists such as taurine or β-alanine, indicating glycine receptor independency. The modulation of calcium responses could be mimicked by several structurally related amino acids (e.g., serine, alanine, or glutamine) and was inhibited in the presence of the neutral amino acid transporter substrate α-aminoisobutyric acid (AIB). We correlated these findings to immunofluorescence glycine uptake experiments which showed a clear glycine uptake which was inhibited by AIB. Furthermore, all amino acids that were shown to modulate calcium responses also evoked AIB-sensitive inward currents, mainly carried by sodium, as demonstrated by patch clamp experiments. Based on these findings, we propose that sodium-coupled neutral amino acid transporters are responsible for the observed glycine modulation of intracellular calcium responses.
Pflügers Archiv - European Journal of Physiology 02/2011; 461(4):481-91. · 4.46 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is a chronic, inflammatory, demyelinating disease of the central nervous system (CNS) in which macrophages play a central role. Initially, macrophages where thought to be merely detrimental in MS, however, recent evidence suggests that their functional phenotype is altered following myelin phagocytosis. Macrophages that have phagocytosed myelin may be less inflammatory and may exert beneficial effects. The presence of myelin-containing macrophages in CNS-draining lymph nodes and perivascular spaces of MS patients suggests that these cells are ideally positioned to exert an immune regulatory role. Therefore we evaluated in this study the effect of myelin-phagocytosing macrophages on lymphocyte reactivity.
Thioglycolate-elicited rat peritoneal macrophages were loaded with myelin and cocultured with myelin-basic protein (MBP) or ovalbumin (OVA) reactive lymphocytes. Lymphocyte proliferation was determined by CFSE-labeling. The role of nitric oxide in regulating lymphocyte proliferation was assessed by addition of an inhibitor of inducible nitric oxide synthase to the coculture. In vivo immune regulation was investigated by treating MBP- and OVA-immunized animals subcutaneously with myelin. Cognate antigen specific lymphocyte proliferation and nitric oxide production were determined 9 d post-immunization.
In this study we demonstrate that myelin-phagocytosing macrophages inhibit TCR-triggered lymphocyte proliferation in an antigen-independent manner. The observed immune suppression is mediated by an increase in NO production by myelin-phagocytosing macrophages upon contact with lymphocytes. Additionally, myelin delivery to primarily CD169+ macrophages in popliteal lymph nodes of OVA-immunized animals results in a reduced cognate antigen specific proliferation. In contrast to OVA-immunized animals, lymphocytes from MBP-immunized animals displayed an increased proliferation after stimulation with their cognate antigen, indicating that myelin-phagocytosing macrophages have dual effects depending on the specificity of surrounding lymphocytes.
Collectively our data show that myelin phagocytosis leads to an altered macrophage function that inhibits lymphocyte proliferation. Additionally, results from this study indicate that myelin-phagocytosing macrophages fulfill a dual role in vivo. On one hand they aggravate autoimmunity by activating myelin-reactive lymphocytes and on the other hand they suppress lymphocyte reactivity by producing NO.
Journal of Neuroinflammation 01/2011; 8:85. · 3.83 Impact Factor
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ABSTRACT: Therapies for multiple sclerosis (MS) reduce the relapse rate but are unable to stop neurological decline. Here, we evaluate the potential of leukemia inhibitory factor (LIF) as a novel therapeutic in diseases with a neurodegenerative and inflammatory component, such as MS. LIF, which can be a proinflammatory cytokine, can also modulate the immune response in a beneficial way. Recent evidence demonstrates a crucial role of LIF in neuroprotection and axonal regeneration as well as the prevention of demyelination. Finally, LIF is an important survival factor for stem cells and neuronal precursors. Therefore, we propose that LIF is a potential therapeutic candidate for MS.
Trends in Molecular Medicine 11/2010; 16(11):493-500. · 10.35 Impact Factor
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ABSTRACT: Myelin-reactive T helper-17 cells are implicated in the pathogenesis of multiple sclerosis (MS). Here, we analyzed the reactivity of peripheral naive and memory conventional CD4(+)CD127(high) T cells (Tconv) of MS patients and healthy controls (HC) towards myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and tetanus toxoid (TT). Proliferative responses of Tconv cells towards MBP, MOG and TT were not significantly different between MS patients and HC. However, MBP and MOG but not TT reactive memory Tconv cells from MS patients, in contrast to HC, produced IL-17. These results suggest that myelin antigen reactive Th-17 cells are enriched in MS patients.
Journal of neuroimmunology 09/2010; 226(1-2):185-91. · 2.84 Impact Factor
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ABSTRACT: Glycine, an important inhibitory neurotransmitter in the mammalian central nervous system (CNS), has been shown to modulate peripheral immune cell responses. In that respect, glycine levels are increased in several neuroinflammatory disorders, such as amyotrophic lateral sclerosis (ALS) and multiple sclerosis (MS). In this study, we show that glycine modulates macrophage effector functions implicated in CNS inflammation and in other, related inflammatory conditions. We demonstrate that glycine does not affect the production of reactive oxygen species but stimulates myelin phagocytosis and the production of the proinflammatory mediators nitric oxide (NO) and tumor necrosis factor (TNF)-alpha by rat macrophages. These effects of glycine are not mediated by the glycine receptor (GlyR) or by glycine transporters (GlyTs), as neither the GlyR antagonist strychnine nor the antagonist of GlyT1 (ALX5407) reverses the observed effects. In contrast, 2-aminoisobutyric acid, a substrate of neutral amino acid transporters (NAATs), inhibits the glycine-mediated enhancement of myelin phagocytosis as well as of NO and TNF-alpha production. In conclusion, our findings demonstrate that glycine modulates macrophage function through activation of NAATs. Glycine may thereby influence immunological processes in inflammatory diseases involving macrophage activation and demyelination, including MS and related conditions associated with altered glycine levels.
Journal of Neuroscience Research 08/2010; 88(11):2420-30. · 2.74 Impact Factor
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ABSTRACT: Myelin-reactive T cells are responsible for initiating the cascade of autoreactive immune responses leading to the development of multiple sclerosis. For better insights into the disease mechanism, it is of major importance to have knowledge on the sites at which these cells are active during disease progression. Herein, we investigated the feasibility of tracking myelin-reactive T cells, upon labelled with SPIO particles, in the central nervous system (CNS) of experimental autoimmune encephalomyelitis (EAE) animals by MRI. First, we determined the optimal labelling condition leading to a high particle uptake and minimal SPIO-Poly-l-lysine (PLL) aggregate formation using Prussian blue staining and inductively coupled plasma spectroscopy measurements. Results from labelling of myelin reactive T cells with low concentrations of SPIO particles (i.e. 25 microg/ml) combined with different concentrations of PLL (0-1.5 microg/ml) showed that increasing amounts of PLL led to augmented levels of free remnant SPIO-PLL aggregates. In contrast, a low PLL concentration (i.e. 0.5 microg/ml) combined with high concentrations of SPIO (i.e. 400 microg Fe/ml) led to a high labelling efficiency with minimal amounts of aggregates. Second, the labelled myelin-reactive T cells were transferred to control rats to induce EAE. At the occurrence of hindlimb paralysis, the SPIO labelled myelin-reactive T cells were detected in the sacral part of the spinal cord and shown to be highly confined to this region. However, upon transfer in already primed rats, T cells were more widely distributed in the CNS and shown present in the spinal cord as well as in the brain. Our study demonstrates the feasibility of tracking SPIO labelled myelin-reactive T cells in the spinal cord as well as the brain of EAE rats upon systemic administration. Furthermore, we provide data on the optimal labelling conditions for T cells leading to a high particle uptake and minimal aggregate formation.
NMR in Biomedicine 07/2010; 23(6):601-9. · 3.21 Impact Factor
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ABSTRACT: Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) with an inflammatory and a neurodegenerative component. The neuropoietic cytokine leukemia inhibitory factor (LIF) is expressed in MS lesions, but its effect on lesion development is far from understood. LIF is an interesting candidate for MS therapy, as it has neuroprotective properties and may also promote the survival of myelinating oligodendrocytes (OLGs). However, therapeutic administration of LIF is complicated by its limited ability to cross the blood-brain barrier and its pleiotropic actions outside the CNS. In this study, lentiviral vectors (LVs) were used to achieve stable expression and secretion of LIF in the CNS of adult mice. CNS-targeted expression of LIF significantly reduced demyelination in a murine model of MS. In addition, local expression of LIF ameliorated clinical symptoms with enhanced efficacy compared to systemic treatment with recombinant protein. These findings demonstrate that gene therapeutic administration of LIF is a promising approach to limit lesion burden and clinical symptoms in neuroinflammatory disease.
Molecular Therapy 04/2010; 18(4):684-91. · 6.87 Impact Factor
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ABSTRACT: The pathological features of multiple sclerosis (MS), a chronic inflammatory disorder of the central nervous system, support an autoimmune etiology. Strong evidence has been provided for a potential functional defect of CD4(+)CD25(+)FOXP3(+) regulatory T cells (Tregs) in patients with relapsing-remitting MS. More recently, alterations in homeostatic parameters related to the development and function of naive and memory-like Tregs were discovered in MS patients. In this review, we evaluate the evidence for disturbed Treg homeostasis in MS and discuss the role of potential compensatory mechanisms in the chronic disease phase. Better insights into the processes underlying the compromised immune regulation in MS patients will be important to understand the potential of Treg-based therapies.
Trends in Molecular Medicine 02/2010; 16(2):58-68. · 10.35 Impact Factor
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ABSTRACT: Glycine is an inhibitory neurotransmitter acting mainly in the caudal part of the central nervous system. Besides this neurotransmitter function, glycine has cytoprotective and modulatory effects in different non-neuronal cell types. Modulatory effects were mainly described in immune cells, endothelial cells and macroglial cells, where glycine modulates proliferation, differentiation, migration and cytokine production. Activation of glycine receptors (GlyRs) causes membrane potential changes that in turn modulate calcium flux and downstream effects in these cells. Cytoprotective effects were mainly described in renal cells, hepatocytes and endothelial cells, where glycine protects cells from ischemic cell death. In these cell types, glycine has been suggested to stabilize porous defects that develop in the plasma membranes of ischemic cells, leading to leakage of macromolecules and subsequent cell death. Although there is some evidence linking these effects to the activation of GlyRs, they seem to operate in an entirely different mode from classical neuronal subtypes.
Frontiers in Molecular Neuroscience 02/2009; 2:9.
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ABSTRACT: Leukemia inhibitory factor (LIF) promotes survival of glial cells and neurons during autoimmune and injury responses in the central nervous system (CNS). While various studies indicate that LIF also modulates ongoing inflammatory responses, data on underlying events are lacking. In this study we demonstrate that LIF modulates macrophage function. LIF inhibits the production of oxygen radicals and TNFalpha and stimulates myelin uptake by macrophages. These effects of LIF are accompanied by activation of the JAK/STAT3 signalling pathway. Our findings demonstrate that LIF has anti-inflammatory properties and enhances myelin clearance, implicating that LIF may be an important factor in CNS inflammatory disease.
Journal of Neuroimmunology 10/2008; 204(1-2):52-7. · 2.96 Impact Factor
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ABSTRACT: Opexa Pharmaceuticals Inc is developing Tovaxin, a trivalent formulation of attenuated myelin-peptide-reactive T-cells, for the potential treatment of multiple sclerosis. Tovaxin is being evaluated in phase II clinical trials. Opexa was previously investigating Tovaxin for the potential treatment of rheumatoid arthritis; however, no development has been reported for this indication since December 2002.
Current opinion in investigational drugs (London, England: 2000) 06/2008; 9(5):534-40. · 3.31 Impact Factor
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ABSTRACT: Patients with relapsing-remitting multiple sclerosis (RR-MS) show a suboptimal CD4(+)CD25(+) regulatory T cell (Treg) function, whereas no Treg alterations are observed in secondary progressive MS (SP-MS) patients. To clarify the difference in Treg activity between early and chronic disease stages in MS, we analyzed the functional capacity and homeostatic parameters of naive CD4(+)CD25(+)CD127(low)CD45RA(+) Tregs (nTregs) and their memory counterparts CD4(+)CD25(+)CD127(low)CD45RO(+) Tregs (mTregs) in untreated MS patients and healthy controls. Interestingly, whereas the suppressive capacity of FACS-sorted nTregs was impaired in both early and chronic MS patients, only the latter group showed a restored mTreg function. Consistent with this observation, chronic MS patients had increased numbers of mTregs as compared with age-matched early MS patients, whereas nTreg frequencies did not differ significantly. TCR excision circle numbers were reduced in nTregs of early MS patients, suggestive of a diminished nTreg thymic output. Moreover, a decreased number of CD31(+) mTregs were observed in early vs chronic MS patients, indicating that inflammatory processes drive the homeostatic turnover of mTregs during the early disease stage. Additionally, early MS patients showed a more restricted nTreg and mTreg TCR BV gene profile as compared with healthy controls and chronic MS patients. Finally, analysis of IFN-beta and glatiramer acetate-treated MS patients showed that these immunomodulatory drugs modify nTreg homeostasis. Taken together, this study provides strong evidence for a disturbed thymic nTreg development and function in MS patients. Moreover, memory Treg but not naive Treg homeostasis recovers during disease progression.
The Journal of Immunology 06/2008; 180(9):6411-20. · 5.79 Impact Factor
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ABSTRACT: While it is widely accepted that myelin reactive T cells are key players in the immunopathogenesis of multiple sclerosis (MS), the initial triggers that turn on these self-reactive T-cells remain to be determined. One mechanism, which is already text book knowledge for a decade, is molecular mimicry by which viral or microbial antigens are able to cross-activate T cells specific for myelin epitopes, the major target in MS pathology. Although proof of concept for this principle was given in animal model studies, evidence for such a mechanism in MS is limited. In this issue, Zhang et al. demonstrate an increased frequency of T cells that cross-react with a wide variety of antigens, a phenomenon termed as T cell degeneracy. While the role of these degenerate T cells in MS remains to be determined the authors now provide new elegant tools to study this T cell population, thus providing a starting point to better understand their function in MS.
European Journal of Immunology 06/2008; 38(5):1190-3. · 5.10 Impact Factor
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ABSTRACT: Macrophages are considered to be the predominant effector cells in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE). Ultra small particles of iron oxide (USPIO) can be used to detect macrophage infiltrates in the CNS with magnetic resonance imaging (MRI). Here, we investigated whether the kinetics of lesion formation in EAE can be visualised by altering the time point of USPIO injection and the time interval between particle injection and MRI. When USPIO are systemically injected 24 h before MRI, hypo intense regions are detected in different brain regions depending on the disease stage. These regions correspond to sites of macrophage infiltration. A more complete visualisation of sites of inflammation is accomplished by USPIO injection at disease onset and postponing MRI to top of disease. This study demonstrates that the distribution pattern and amount of inflammatory lesions detected with USPIO, depends on timing of USPIO administration and subsequent MRI. These findings are important for a correct application and interpretation of USPIO dependent contrast imaging of CNS inflammation.
Journal of Neuroimmunology 04/2008; 195(1-2):1-6. · 2.96 Impact Factor
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ABSTRACT: Leukemia inhibitory factor (LIF) promotes the survival of oligodendrocytes (OLG) both in vitro and in an animal model of multiple sclerosis. Here, we show that LIF protects mature rat OLG cultures selectively against the combined insult of the proinflammatory cytokines interferon-gamma and tumor necrosis factor-alpha, but it does not protect against oxidative stress nor against staurosporine induced apoptosis. We further demonstrate that LIF activates the janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) and the phosphatidylinositol 3 kinase/Akt pathway in mature OLG. We show that LIF protection is independent of suppressors of cytokine signaling and Bcl-2 mRNA expression levels. To gain further insight into the protective mechanism, a quantitative proteomic approach (DIGE) was applied to identify differentially expressed proteins in LIF-treated OLG. Our results indicate that LIF induces a shift in the cellular machinery toward a prosurvival execution program, illustrated by an enhanced expression of isoforms of the antiapoptotic molecule 14-3-3. These data provide further insight into the mechanisms of LIF-mediated protection of mature OLGs.
Proteomics 04/2008; 8(6):1237-47. · 4.43 Impact Factor
